What should have been a very good day for Medicines Company was marred by one factor: the unpredictability of how investors will react to news from clinical trials. Confirmation that a single dose of the RNA interference project ALN-PCSsc can significantly lower cholesterol for six months was marred by a single death and a case of liver enzyme elevations.
Release of detailed data from the Orion-1 trial kicked off a volatile trading period as shares rose initially and then fell quickly on news of the trial death, only to end the day on a very routine 1% gain. A single death in this high-risk patient group should not be surprising, and Medicines Company justifiably plans to advance the agent into pivotal trials.
Good day, bad day
Orion-1 tests whether a single jab of ALN-PCSsc, now known as inclisiran, can significantly lower low-density lipoprotein cholesterol (LDL-C) better than placebo up to 180 days. Most of the 497 patients in the trial were on statins or other lipid-lowering therapies as background treatments.
Medicines Company released interim data at the AHA meeting yesterday, intending to show effectiveness through day 90. A 300mg dose reduced LDL-C by an average of 50% at that time, and for the 21 patients at that dose who have been followed for 180 days the reduction has persisted, at 43%. The effect was higher for 28 patients who received a second dose of inclisiran at day 90, who saw a 52% reduction at day 180.
This compares somewhat favourably to new drug Repatha, which saw LDL-C reductions of 22-64%, depending on the dose frequency and population.
All of this would have made for a good day for investors if not for the additional disclosure that one patient taking inclisiran had died of a heart attack 107 days after the first dose. As shares started falling, executives went into damage-control mode, pointing out that at least one death would be expected in this population with established cardiovascular disease and high LDL-C.
In any case, blinded trial investigators said the death was not linked to study medication. A patient with liver enzyme elevations, meanwhile, had recently seen an increase in background statin dose, and it resolved with a subsequent dose reduction.
A 7% share price rise in early trading today suggests that investors have grown more comfortable that these two cases do not represent a safety signal.
Safety scare aside, there is little in the data to rebut the bull case for inclisiran, which like Repatha from Amgen and Praluent from Sanofi and Regeneron regulates LDL-C levels in the body by improving liver metabolism through the PCSK9 pathway. Medicines Company has always rested the argument for their product on less frequent dosing – infrequently enough that patients could get an injection with regular physician check-ups – and the potential value that would provide for payers (Interview – Medicines Company looks away from the hospital bed, September 8, 2015).
Chief executive Clive Meanwell reiterated this point during a conference call with analysts discussing the Orion-1 results, when he spoke of a “commitment to value-based pricing.”
The value proposition will need to be borne out in the long run with cardiovascular outcomes trials like those in which Repatha and Praluent are now being reviewed, although Amgen and Sanofi have provided a model for quick approval in small, defined populations. Mr Meanwell said Medicines Company’s $600m in cash would be sufficient to get inclisiran through phase III trials to approval. But the sum is far from sufficient for an outcomes trial that would number in the tens of thousands of patients.
The first signs of whether LDL-C lowering through the PCSK9 pathway can prevent cardiovascular death or hospitalisation will emerge early next year when the Repatha Fourier trial reads out, probably early in 2017. At AHA, Amgen raised the hopes of positive data when its Glagov trial showed through intravascular ultrasound that patients taking Repatha and statins saw a significant reduction in the volume of arterial plaque compared with patients taking statins.
Whether any of these new agents can show that their value matches their price will be down to the findings of these big outcomes studies. If they fail, Medicines Company will find it considerably harder to source funds to test its own agent in a similar setting.