Armed with stellar — if niche — PhIII data, Regeneron steers 'breakthrough' cholesterol drug to post-PCSK9 waters
Two years after nabbing a breakthrough therapy designation for evinacumab, Regeneron has a slate of stellar Phase III data to buttress its case for offering the antibody to patients whose LDL cholesterol are so out of control that they may need something even stronger than PCSK9 inhibitors.
The drug treats a rare condition called homozygous familial hypercholesterolemia, or HoFH, in which patients have mutations in both copies of either PCSK9, LDLR or APOB genes. Regeneron scientists found two decades ago that the angiopoietin-like protein 3 (ANGPTL3) blocks lipoprotein lipase and endothelial lipase from regulating lipoprotein metabolism. By inhibiting this protein, Regeneron’s theory goes, they can unleash the enzymes to bring down the dangerously high levels of LDL cholesterol.
According to the topline results, it worked — better than available HoFH therapies.
Investigators tracked a 49% reduction in LDL cholesterol from baseline among those taking the drug, compared to a 2% increase for placebo (p<0.0001). And that’s on top of the other lipid lower therapies the patients were already taking, including statins, PCSK9 inhibitors, ezetimibe, LDL apheresis and lomitapide. On average, the absolute changes were 132 mg/dL and 3 mg/dL, respectively (p<0.0001).
That could set it up to treat patients who have failed Repatha, Amgen’s PCSK9 inhibitor, which is approved for the indication and has previously shown LDL cholesterol reduction of 31%, Cowen analyst Yaron Werber wrote. Repatha is now priced at $5,850 a year after insurers won a pricing tug-of-war, prompting a 60% discount.
Moreover, while the 65 patients began the trial with average LDL cholesterol levels of 255 mg/dL, 47% of those receiving evinacumb saw their measurements go down to or below the healthy 100 mg/dL threshold. In the placebo (again, plus other therapies) group, 23% achieved the same (p=0.0203).
Notably, about a third of the drug arm had the most severe form of HoFH — patients who were essentially not responding to any other treatments.
Regeneron president and CSO George Yancopoulos added that the results bode well for another ongoing trial targeting severe, refractory hypercholesterolemia, which spans both the inherited (but heterozygous) and “environmental” forms of the disease. While Praluent, the PCSK9 drug they share with Sanofi, is approved to treat HeFH, some continue to experience persistently high cholesterol despite existing lipid management therapies.
“These evinacumab Phase 3 results bring hope to those who need it most” is how FH Foundation founder and CEO Katherine Wilemon put it.
The small size of this patient population, though — Regeneron estimates 1,300 cases of HoFH in the US — may further strain evinacumab’s commercial hopes as payers continue to debate the value of cardiovascular advances.
Werber calls the data “highly encouraging” and acknowledges the clinical need. By his estimates, US peak sales should reach the range of $200 million to $400 million while Europe will bring in similar sales numbers.
So evinacumab should be attractive but the key question will be what will payers be willing to pay for this orphan segment. This is especially relevant for evinacumab given the tremendous pricing and access pressures that the anti-PCKS9 class is facing.
The company expects to begin submitting data to the FDA in 2020.