If Amgen had a bad day on Friday with the release of long-awaited outcomes data for its cholesterol drug Repatha, then consider the Medicines Company. Its phase II project modulating the same biological pathway as Repatha is showing similar effectiveness in lowering LDL, and has some lingering safety concerns to boot.
Amgen’s Fourier trial of Repatha has left the market wondering how much the expensive new PCSK9-blocking agents can improve on treatment with statins, and nine-month data from the Orion-1 trial of the Medicines Company’s inclisiran at this point do not look as though they will change the debate. Inclisiran has the advantage of dosing twice a year, but of course its durability is the result of an RNA interference technology that has had its own troubles (Alnylam failure puts RNAi under the spotlight again, October 6, 2016).
On to phase III
In another context, the inclisiran data would be taken as a modest positive in that they confirm previous findings and provide additional evidence to advance into phase III. The trial tested six dosing regimens, three of them a single injection and three two injections 90 days apart; the company now has efficacy data 240 days after the first injection.
When combined with statins, the highest single dose of inclisiran, 500mg, and the highest two-dose regimen, 300mg, both achieved a 57% reduction in LDL at 240 days. Three cases of elevated liver enzymes were detected in patients taking inclisiran and one in a patient on placebo (AHA – Medicines Company’s should-have-been day falls flat, November 16, 2016). The company said the adverse event findings should raise no safety concerns.
But coming hours after the Repatha outcomes results – which found that the Amgen drug combined with a statin reduced LDL by 59% versus statin alone – the inclisiran data look underwhelming. Repatha's LDL reduction yielded a 15% drop in the relative risk of cardiovascular events and death, less than many were expecting (ACC – No Repatha of glory, March 17, 2017).
Repatha patients achieved a median LDL of 30mg/dl; by comparison, in the 300mg two-dose inclisiran regimen, 48% of patients achieved an LDL level of 50mg or less at day 180.
The 20% drop in Medicines Company’s shares early in the day was a response to Repatha data from the Fourier trial, although they recovered to 8% down at close after the release of the Orion-1 study.
Just like Amgen's leadership, Medicines Company executives were quick to characterise Fourier as a success to support their plans for a phase III programme in which the 300mg two-dose regimen followed by twice-yearly injections will be advanced simultaneously in LDL-lowering efficacy trials and a longer-term outcomes study.
“Lower is better,” the Medicines Company's chief executive, Clive Meanwell, said of LDL.
Finding a partner
Repatha and the competing Praluent from Sanofi and Regeneron both achieved approval on efficacy studies that did not include robust outcomes findings, but in both cases outcomes trials were initiated to argue for expanded use of the agents.
The Medicines Company plans to begin an outcomes trial called Orion-4 alongside its efficacy studies, examining the use of inclisiran in patients with starting LDL of around 130mg/dl, more elevated than the median 92mg/dl baseline of the Fourier population.
Mr Meanwell has been clear for some time that his company does not plan to fund a huge outcomes trial itself because it cannot afford $1bn, and in a call with investors yesterday he reiterated this message. Potential partners will no doubt want to look closely at how payers respond to Fourier before signing an agreement.
The Medicines Company has bet its future on inclisiran, and it might now have to work hard to convince a strategic partner to join its gamble.