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DRugwatch Blog > March 2014 > Ivabradine: Has this Agent Really Got Physicians’ Hearts Stopping or will Further Trials Be Required

Ivabradine: Has this Agent Really Got Physicians’ Hearts Stopping or will Further Trials Be Required for a U.S. Launch?

Joseph DwyerGraeme GreenContributors: Joseph Dwyer and Graeme Green

In the realm of cardiovascular agents, the heart failure segment currently represents a hotspot for product development. With around 30 compounds in various stages of development, ranging from Phase I to pre-registration, drug companies recognize that this is a growing disease market. Ivabradine (Servier’s Procoralan) represents one of the most recent entries into the heart failure market, having found use in both the treatment of chronic heart failure (CHF) and stable angina in Europe.

Ivabradine is a heart-rate-lowering agent that selectively inhibits the sinus node I(f) pacemaking current, thereby decreasing myocardial oxygen demand without effecting inotropism or blood pressure. Backed by sound clinical data and a fairly benign safety profile, ivabradine has enjoyed moderate use within the countries it has launched in.
In 2005, ivabradine received its label for the treatment of chronic stable angina in patients who were intolerant of—or inadequately controlled by—beta blockers and whose heart rate exceeded 60 beats per minute (in sinus rhythm). This indication was acquired on the back of the 10,917 patient BEAUTIFUL study. Although, ivabradine did not significantly reduce the composite primary end point of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure, it did significantly reduce the secondary end points of hospital admission for fatal/non-fatal myocardial infarction and coronary revascularization (See Table) (Fox K, 2008). 
 


Expansion into a European CHF label was driven by the favorable outcomes noted in the 6,505 patient SHIFT trial, which looked at ivabradine in addition to standard care, including beta-blocker therapy, in patients with systolic heart failure and elevated heart rate (≥75 bpm). Ivabradine significantly reduced the primary end point, a composite of cardiovascular death or hospital admission for worsening heart failure (See Table) (Swedberg K, 2010). Although physicians cited using ivabradine off-label in CHF patients before its official label expansion into CHF, the SHIFT trial has helped ivabradine gain traction in use in Europe.

Ivabradine has not been launched in the United States and Japan, where Servier has a limited commercial presence. However, in 2013, Servier announced a commercial partnership with Amgen. Under this deal, Amgen obtained the U.S. marketing rights for ivabradine for $50M plus milestones and royalties (Servier, press release, July 9, 2013). Similarly, in Japan, Servier has teamed up with Ono pharmaceuticals to develop and commercialize this agent (Ono Pharmaceutical, press release, September 14, 2012). The prospect of ivabradine’s launch in the United States has generated excitement among thought leaders in this region. However, some sources have reported uncertainties regarding whether ivabradine’s U.S. approval will be allowed to move forward without a clinical trial for heart failure in the United States.
According to a number of experts, one issue revolves around the patient population employed in the SHIFT study. This study was primarily composed of European patients. Similarly, the BEAUTIFUL study did not employ any U.S. study sites. Therefore, some experts doubt whether these results can be applied to the more diverse U.S. population. Another issue related to the low doses of beta-blockers that were administered to many patients in the trial. Ideally, titration onto maximal doses of beta-blockers should have taken place before using ivabradine.

However, the expected CHF filing for ivabradine in the United States in 2014 would indicate that Amgen believes that no further trials will be required. We note that most of the talk has circled around an approval for CHF. We believe this focus reflects the higher level of unmet need in this patient population (versus the stable angina population) and the more compelling level of data from the SHIFT study.

A number of thought leaders interviewed by Decision Resources agree with the notion that ivabradine’s approval will readily move forward in the United States. One U.S. expert comments, “I don’t see why another trial would be required. The data look very good and the FDA accepts European data.”  While we do forecast a U.S. launch of ivabradine for CHF we have identified several factors that will impact its uptake in this region.

While cardiologists express excitement about the benefits ivabradine has to offer—especially given the reductions in heart failure hospitalizations and mortality demonstrated in the SHIFT trial—this therapy will be restricted to second-line use, as has been the case in the Europe. European thought leaders communicate that ivabradine has been reserved for situations where the rate-controlling effects of beta blockers are insufficient or when patients are intolerant to beta blockers. Ivabradine will also be restricted to CHF patients in sinus rhythm with a resting heart rate of ≥75 bpm. Therefore, ivabradine’s second-line status and restriction to certain patient populations will temper its uptake in the U.S. CHF market. Despite its somewhat niche segmentation, ivabradine is still viewed as an efficacious and useful agent which U.S. physicians are excited about. As such, we expect ivabradine to perform well in the US market and mark a successful entrance into the cardiovascular space for Amgen.  Amgen does not currently hold a position in the cardiovascular market, but we consider it to have some interesting R&D programs that fall under this therapy area notably its proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab and their cardiac myosin activator omecamtiv mecarbil. Importantly, gains made with ivabradine will support future cardiovascular launches.  

Coming Soon:
DecisionBase: Chronic Heart Failure (April 2014)
Pharmacor: Heart Failure [AHF & CHF] 2014 (September 2014)


Business Insights Analyst Joseph Dwyer and Senior Analyst Graeme Green are part of the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.

References:
Fox K, et al. 2008. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Sep 6;372(9641):807-16.
Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.

Posted on: 3/27/2014 11:24:21 AM | with 0 comments


Tags: Cardiovascular, Graeme Green, Joseph Dwyer

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