The FDA approved Corlanor (ivabradine) to reduce the risk of hospitalization for worsening heart failure (HF), marking the first win in Amgen Inc.'s small but ambitious cardiovascular (CV) franchise. Approval was limited to patients with stable, symptomatic chronic HF with left ventricular ejection fraction ≤35 percent who are in sinus rhythm with a resting heart rate ≥70 beats per minute and who are on maximally tolerated doses or have a contraindication to beta blockers.

With approval in just a subset of HF patients, J.P. Morgan analyst Cory Kasimov suggested the product "is unlikely to materially move the needle" for Amgen. He cited 2018 consensus estimates of $190 million and a J.P. Morgan estimate of $165 million in sales. Still, the Thousand Oaks, Calif.-based biotech estimated approximately 1 million patients in the U.S. are medically eligible for treatment with the drug, according to Kasimov.

Hearts were hardly racing on Wall Street. After moving slightly higher Wednesday evening following the after-hours approval, shares of Amgen (NASDAQ:AMGN) opened lower Thursday morning, gaining $1.40, to close at $166.87. Investors were more focused on prospects for Amgen's potential blockbuster Repatha (evolocumab), which could become the first drug to emerge from the much anticipated protein convertase subtilisin/kexin type 9, or PCSK9, inhibitor class.

Still, the nod to Corlanor represented the first FDA approval of a chronic HF drug in nearly a decade. Corlanor was first approved in the EU in 2005 for symptomatic treatment of stable angina and in 2012 for chronic HF in patients with elevated heart rate. All told, the drug was previously approved in more than 100 countries.

Amgen gained U.S. rights to the product, known elsewhere as Procoralan, through a 2013 collaboration with Les Laboratoires Servier SA, of Paris, for $50 million up front and undisclosed milestone and royalty payments, according to Thomson Reuters Recap. The same deal gave Amgen an exclusive option to develop and commercialize Servier's S38844, a small-molecule CV agent, in the U.S.

Corlanor blocks the hyperpolarization-activated cyclic nucleotide-gated channel responsible for the cardiac pacemaker, which regulates heart rate, and reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If, or "funny," current to slow the heart rate without affecting ventricular repolarization or myocardial contractility.

Approval was based on global clinical trial data, including a multicenter, randomized, double-blind, placebo-controlled outcomes trial. The phase III SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) compared Corlanor to placebo on top of standard of care (SOC), including beta blockers, in more than 6,500 patients. Results showed Corlanor significantly reduced the risk of the primary composite endpoint of hospitalization or CV death for worsening HF, with 18 percent relative risk reduction.

The most common adverse events in SHIFT, occurring in ≥1 percent of patients on Corlanor compared to placebo, were bradycardia (10 percent vs. 2.2 percent), hypertension (8.9 percent vs. 7.8 percent), atrial fibrillation (8.3 percent vs. 6.6 percent) and luminous phenomena (2.8 percent vs. 0.5 percent).

Corlanor was granted FDA priority review and fast track designation. Amgen said the drug is expected to be available to patients in approximately one week, although the company did not disclose pricing.

UPSIDE FROM COMMERCIAL EFFORTS, MARKETING SYNERGY

Analysts predicted Corlanor would be used generally in addition to SOC treatment. In a first glance, RBC Capital Markets analyst Michael Yee predicted Corlanor could ring up $300 million to $500 million in peak sales "due to greater commercial efforts and marketing synergy" in preparation for launch of Repatha, which is in a race with alirocumab, from Regeneron Pharmaceuticals Inc. and partner Sanofi SA, to become the first PCSK9 to market. (See BioWorld Today, April 1, 2014, and July 31, 2014.)

After Regeneron, of Tarrytown, N.Y., picked up a priority review voucher for alirocumab from Biomarin Pharmaceutical Inc., of Novato, Calif. – splitting the $67.5 million tab with partner Sanofi SA, of Paris – Amgen struck back by seeking an injunction to block alirocumab's manufacture and sale over alleged infringement on Repatha's patents. Both candidates remain under regulatory review. (See BioWorld Today, Aug. 1, 2014, and Oct. 20, 2014.)

Last month, Amgen presented one-year data from the phase II (OSLER-1) and phase III (OSLER-2) open-label extension studies at the American College of Cardiology's annual scientific session in San Diego showing the cholesterol-lowering Repatha plus SOC treatment reduced low-density lipoprotein cholesterol by 61 percent (95 percent CI: 59 percent-63 percent, p < 0.0001), to a median of 48 mg/dL, for an absolute reduction of 73 mg/dL (95 percent CI: 71 percent-76 percent). (See BioWorld Today, March 17, 2015.)

Pre-specified exploratory endpoints of adjudicated CV events from the ongoing open-label OSLER studies also showed Repatha lowered those events – death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke and transient ischemic attack or HF requiring hospitalization – by 53 percent (0.95 percent Repatha plus SOC; 2.18 percent SOC) over the one-year analysis period.

Although many analysts were already looking beyond Wednesday's FDA approval to Repatha, Piper Jaffray analyst Joshua Schimmer wrote in a hot comment that Corlanor could play an important role in the evolution of HF treatment, "and it also represents a key first step in the company building out its CV franchise," he pointed out. Priced at a monthly wholesale acquisition cost of $375, or the equivalent of $4,500 per patient per year, Corlanor could achieve peak sales of $1 billion, Schimmer predicted.

"We expect AMGN to ramp up its [key opinion leader]-targeting efforts with this approval in hand and take advantage of its lead-time over [Novartis] LCZ696, which has a PDUFA date in August," he wrote.

Piper Jaffray analyst Charles Duncan offered another spin in his hot comment, noting that Corlanor's approval could offer an upside for Cytokinetics Inc., of South San Francisco, which is partnered on Amgen's third CV asset, omecamtiv mecarbil. (See BioWorld Today, Jan. 4, 2007, and May 27, 2009.)

The oral form of the drug, a small-molecule activator of cardiac myosin, is in the ongoing phase II COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure) study, scheduled to report data later this year, according to Cortellis Clinical Trials Intelligence. In 2013, the phase II ATOMIC-AHF (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) trial, which tested the intravenous formulation in 613 acute HF patients, failed to hit the primary endpoint. At the time, both companies vowed to press on with the 420-patient COSMIC-HF. (See BioWorld Today, Sept. 4, 2013.)

"We think the ivabradine result bodes well for omecamtiv's future on a number of fronts," Duncan wrote., reiterating an "overweight" rating and $13 price target for shares of Cytokinetics (NASDAQ:CYTK), which lost 4 cents Thursday to close at $7.13.