Dive Brief:

• Releasing full data from a multi-year study of a fish oil drug this weekend, Amarin incited a spirited cardiology debate around Vascepa's reported heart benefits and the strength of the study's findings.
• Vascepa hit its primary endpoint and nearly all its secondary ones in the Phase 3 study called REDUCE-IT, showing a 25% relative risk reduction in the first occurrence of major adverse cardiovascular events. However, some cardiologists have voiced questions and hesitancy on the mineral oil placebo used in the control, which appeared to raise the control group's average levels for two key biomarkers.
• Amarin's stock fell about 15% in the first hours of trading Monday morning after opening down 4%. Even with the drop, Amarin's stock is up about 350% on the year, boosted by the prospect of a potential blockbuster heart drug in the making. 

Dive Insight:

Amarin started its REDUCE-IT study of Vascepa (icosapent ethyl) in 2011 with more than 8,000 statin-treated adults with high cholesterol levels, defined as an LDL-C between 41 to 100 mg/dL.

The results were presented to a packed audience at the American Heart Association's annual conference on Nov. 10 and also published in The New England Journal of Medicine. 

The risk reductions found were impressive and potentially practice-changing, according to some cardiologist observers. In addition to the main 25% risk reduction on a five-component composite of major adverse cardiovascular events, Vascepa also reduced the risk of cardiovascular death, heart attack or stroke by 26% — bolstering the initial findings presented in September. 

But while the results were compelling, some experts noted increases to certain biomarkers within the control group, creating a bearish investor theory that helped drive the stock down 15% in the first few hours of market trading.

The main concern centered around the mineral oil placebo, not Vascepa itself. Among the control group, two key biomarkers both increased: LDL, commonly known as a measure of bad cholesterol, and hsCRP, or high sensitivity C-reactive protein which tracks background levels of inflammation.

For those taking the mineral oil control, LDL rose 10% (compared to an average 3% increase with Vascepa) and hsCRP went up 30% (while Vascepa patients went down by about 18%). 

If these biomarkers were affected by the control, meaning the placebo affected patients' LDL and hsCRP levels instead of acting as a baseline to test against, that could dilute the relative risk reductions Amarin has touted as the key takeaways from REDUCE-IT. 

However, further subgroup analysis may help clear up what exactly happened with these biomarkers, and the results could still stand regardless on the Vascepa's general efficacy and safety.

Ty Gluckman, the medical director for the Center for Cardiovascular Analytics, Research and Data Science at Providence St. Joseph Health in Portland, Oregon, said the HSCRP and LDL increases in the control arm were "unusual" but believed that could have played a "very small role" in the overall results.

He added that, from a clinician perspective, the absolute increase matters more than the relative for these biomarkers. For example, the 30% uptick in hsCRP was an increase from 2.1 milligrams per liter to 2.8 milligrams per liter. 

"Just because it's statistically significant does not mean it's clinically meaningful," Gluckman said on the CRP, LDL controversy on a Jefferies investor call Monday.

Additionally, John Osborne, director of State of the Heart Cardiology, said the biology of LDL could explain the raise, particularly with longer clinical trials. REDUCE-IT spanned nearly five years, with a median follow-up of 4.9 years. 

"The biology of LDL is, with time, it goes up," he said on the Jefferies call. "As we get older, we get fatter. We get grayer."

As Amarin goes forward with its plan to file for an expanded label of Vascepa with the Food and Drug Administration, how it explains and further analyzes these disparities could become an important question.