No sooner did cholesterol-lowering drug Repatha receive approval from the FDA than news emerged of a potential threat on the horizon.
Promising phase I data from ALN-PCS, an Alnylam RNA interference project modulating the same PCSK9 pathway as Amgen’s antibody, was released at the European Society of Cardiology meeting yesterday, and suggests that the project might offer the potential for once-quarterly dosing compared with every two weeks for Repatha and Sanofi’s Praluent. The Medicines Company, ALN-PCS's licensee, said it would begin phase II trials by the end of the year and pivotal studies in 2017, an announcement that drove shares up 13% to $37.99 in early trading today.
The potential for less frequent dosing “changes how we think about cholesterol management,” Clive Meanwell, the Medicines Company’s chief executive, told EP Vantage. “It moves it from, ‘I have to take my tablet today’ to ‘I’ll do it at the same time as my flu shot.’
“The economic model would potentially allow us, every time you have this drug, to have a nurse standing next to you. That’s a big reinforcer. Then you change adherence,” he said.
The data comes from trials seeking to identify the best dose for ALN-PCS, but with secondary endpoints focussing on the lowering of the harmful low-density lipoprotein (LDL) that leads to atherosclerotic disease, as well as knockdown of PCSK9. Across the doses, a 44% reduction in LDL was measured at day 140; investigators judged the agent as generally well tolerated and adverse events as mild or moderate.
The agent targets PCSK9, a protein that reduces the number of receptors in the liver that assist in the removal of LDL in the bloodstream. Repatha and Praluent are antibodies that PCSK9 to assist in LDL metabolism; ALN-PCS impedes PCSK9 synthesis in cells.
Based on the results, the Medicines Company and Alnylam suggested the possibility of bi-annual dosing – maybe more often than a flu shot, but infrequently enough that it could be scheduled as part of regular physician appointments.
The statement on bi-annual dosing took analysts by surprise, with Leerink’s Joseph Schwartz raising his price target from $40 to $53.
The phase II Orion trial in atherosclerotic disease and familial hypercholesterolemia will most likely centre on two 300mg doses given 28 days apart, but may include a 200mg dose and a higher dose at 400 or 500mg.
The PCSK9 space has found itself suddenly filled in the past few months with European and US decisions for both Praluent and Repatha. They are expensive agents at more than $14,000 a year.
The US label restricts use to patients with genetically linked LDL elevations as well as the most severely ill, and payers are not likely to support their use outside of that setting at least until cardiovascular outcomes trials report. Should those be positive, use will most likely be restricted to patients shown to be resistant to statins.
Mr Meanwell suggested that ALN-PCS would have lower production costs, suggesting that it could differentiate on price. This is forward thinking on the Medicines Company’s part, well in advance of robust confirmatory data. Given the controversy generated this year by Sanofi and Amgen, this is a wise move.