Cholesterol lowering drugs: the race is on!

Dr Jay Edelberg, Head of the PCSK9 Development and Launch Unit at Sanofi discusses the ongoing clinical trial assessing PCSK9 inhibitors for use in patients with high cholesterol, in our cardiovascular themed month.

A high concentration of LDL particles is strongly associated with cardiovascular disease, and is present in an estimated 110 million Americans. Currently available lipid-lowering therapies provide benefit, however there are a large number of patients globally who do not achieve their LDL-C goal with such treatments, in addition to many who cannot tolerate such therapy.

An exciting new development for those patients exists in the form of PCSK9 inhibitors.

Currently, the race to develop these inhibitors, which could potentially revolutionise the field of heart disease, is on between large pharma companies, with treatments not expected to come to market for a few years yet.

Results so far are promising, and Sanofi in co-development with Regeneron Pharmaceuticals, is leading the way with the commencement of its phase 3 trial in this area, ODYSSEY.

pharmaphorum’s Rebecca Aris spoke with the head of the PCSK9 Development and Launch Unit at Sanofi, Dr Jay Edelberg, on what we can expect from this trial and the potential implications of this treatment.

Interview summary

RA: Dr Edelberg, could you please tell us more about the rare genetic mutation that leads to low cholesterol and how we came to our current understanding of this mutation?

JE: Human genetic studies provide strong target validation for the role of PCSK9 in modulating LDL cholesterol (LDL-C) levels and the risk of coronary heart disease (CHD).

In 2006, Cohen and co-workers described in the New England Journal of Medicine that loss-of-function PCSK9 mutations are associated with low LDL-C and low prevalence of cardiovascular events. They reported that in Atherosclerosis Risk in Communities (ARIC) study the incidence of CHD over a 15-year interval varied according to the presence or absence of sequence variants in the PCSK9 gene.

Of the 3363 black subjects examined, 2.6 % had nonsense mutations in PCSK9; these mutations were associated with a 28 % reduction in mean LDL-C and an 88 % reduction in the risk of CHD. Of the 9524 white subjects examined, 3.2 % had a sequence variation in PCSK9 that was associated with a 15 % reduction in LDL-C and a 47 percent reduction in the risk of CHD.

RA: As head of Sanofi’s PCSK9 development and launch division, what can you tell us about the ODYSSEY trial and when can we expect to hear results from it?

JE: We are excited to rapidly progress towards initial results from our ongoing phase 3 program (ODYSSEY) with our investigational PCSK9-inihibitor alirocumab.

“PCSK9 inhibition represents an exciting new development in particular for those patients.”

Despite benefits with currently available lipid-lowering therapies, there are a large number of patients worldwide who are unable to achieve their LDL-C reduction goals with statin therapy as well as a large number who cannot tolerate statin therapy.

PCSK9 inhibition represents an exciting new development in particular for those patients.

In 2012, we reported encouraging results with alirocumab from phase 2, demonstrating that alirocumab can lower LDL-C by about 70% on top of statins and bring almost 100% of patients to their LDL-C goal with an acceptable safety profile.

The ODYSSEY program studies alirocumab in the following patient populations:

• patients with Heterozygous Familial Hypercholesterolemia (HeFH) who are inadequately controlled by current lipid-modifying therapy;

• patients with primary hypercholesterolemia unable to tolerate statins;

• and high cardiovascular risk patients with primary hypercholesterolemia.

These three patient populations with uncontrolled hypercholesterolemia would particularly benefit from improved treatment to reduce their cardiovascular risk and we look forward to see phase 3 results with alirocumab.

About ODYSSEY

The global phase 3 ODYSSEY program with alirocumab will enroll more than 22,000 patients and currently includes 11 clinical trials of alirocumab both in combination with other lipid-lowering agents and as monotherapy. The ODYSSEY program includes the following patient populations: patients with HeFH who are inadequately controlled by current lipid-modifying therapy; patients with primary hypercholesterolemia unable to tolerate statins; and high cardiovascular risk patients with primary hypercholesterolemia. These patient populations with uncontrolled hypercholesterolemia would particularly benefit from improved treatments to reduce their cardiovascular risk. The ODYSSEY program includes the following trials:

• ODYSSEY MONO: The primary objective of this study was to demonstrate the safety and efficacy of alirocumab as a monotherapy in patients with primary hypercholesterolemia. All patients will be treated for 6 months.

 

“The global Phase 3 ODYSSEY program with alirocumab will enroll more than 22,000 patients…”

• ODYSSEY FH I, FH2, and HIGH FH: These three studies evaluate alirocumab as an add-on treatment in patients with HeFH who are not adequately controlled with their current lipid-modifying therapy. All patients will be treated for 18 months.

• ODYSSEY COMBO I and COMBO II: These two studies evaluate alirocumab as an add-on therapy in patients with primary hypercholesterolemia and at high cardiovascular risk and not adequately controlled with their lipid-modifying therapy. Patients in the COMBO I study will be treated for one year, while patients in the COMBO II study will be treated for two years.

• ODYSSEY ALTERNATIVE: The primary objective of this study is to demonstrate the safety and efficacy of alirocumab in comparison with ezetimibe in patients with primary hypercholesterolemia unable to tolerate statins. Patients in this study will be treated for 18 months.

• ODYSSEY OPTIONS I and OPTIONS II: The primary objective of these studies is to assess the efficacy and safety of alirocumab as an add-on in patients with primary hypercholesterolemia at high cardiovascular risk or with HeFH who are not adequately controlled on statins, in comparison to several other lipid-lowering strategies. The duration for both studies will be 6 months.

• ODYSSEY LONG TERM: This study will evaluate the long-term safety and tolerability of alirocumab in patients with hypercholesterolemia at high cardiovascular risk or patients with HeFH inadequately controlled with their current lipid-modifying therapy. All patients will be treated for 18 months.

• ODYSSEY OUTCOMES: The primary objective of this study is to compare the effect of alirocumab with placebo on the occurrence of cardiovascular events (composite endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization) in patients who have experienced a recent acute coronary syndrome (ACS) event.

RA: What could be the implications on public health if PCSK9 inhibitors were approved for use?

JE: Despite cholesterol-lowering therapy, an estimated 66% of all adults in the US who are treated do not achieve their LDL-C goal. It is also estimated from NHANES data that 23% of high risk patients who are treated do not achieve goal of <100 mg/dL, and 76% of high risk patients do not achieve LDL-C <70 mg/dL. Approximately 80% of patients with heterozygous familial hypercholesterolemia (HeFH) have poorly controlled hypercholesterolemia and do not achieve LDL-C <100 mg/dL.

Should PCSK9-inhibitors be approved, we hope that they will contribute to improving today’s situation for those patients.

“…an estimated 66% of all adults in the US who are treated do not achieve their LDL-C goal.”

RA: What are the challenges associated with developing biologic treatments such as PCSK9 inhibitors?

JE: Sanofi has a long-standing track-record and broad expertise in delivering subcutaneously administered biologic treatments, including insulins, such as Lantus, and anti-thrombotics, such as Lovenox. With this heritage, Sanofi is co-developing with Regeneron a number of specific biologics targeted at a variety of disease areas with high unmet medical need.

RA: With average healthy adults LDL usually at over 100, what are the health implications of a treatment that could lower it to below 25?

JE: Lowering LDL-C levels to specific and individualized goals is the primary treatment objective for patients with hypercholesterolemia with or without CVD. Our Odyssey program with alirocumab was developed in coordination with major Health Authorities around the world and with the input from high level experts.

RA: When can we expect to see PCSK9 inhibitors on the market?

JE: We are excited with the ongoing phase 3 program Odyssey with alirocumab and look forward to reporting initial results from phase 3 later this year. We hope to contribute with alirocumab to the management of LDL-C and CV risk in the future. Please understand, that we won’t speculate about subsequent steps prior to phase 3 results and important regulatory milestones.

 

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About the interviewee:

Dr Jay Edelberg is Vice President and Head of the PCSK9 Development and Launch Unit at Sanofi.

Previously, Dr Edelberg held various senior pharmaceutical positions at top pharma companies, Bristol-Myers Squibb and GlaxoSmithKline. He was also the Associate Professor of Medicine at Weill Medical College of Cornell University between 1999 and 2006.

What other cardiovascular drug developments are you interested in?