Whatever worries lingered around The Medicines Company’s longer-lasting PCSK9 cholesterol fighter should be largely cleared up now, thanks to a set of pivotal phase 3 data that shows the drug is at least as safe and effective as its two marketed rivals.
In a 1,617-patient study, inclisiran cut bad cholesterol by 54% when added to statin therapy, a number comparable to the 50%-plus stats put up by existing PCSK9 inhibitors—Amgen's Repatha and Sanofi and Regeneron's Praluent—in their own pivotal trials.
Industry watchers have been more focused on the med's safety profile, though, because it uses an Alnylam Pharmaceuticals delivery platform recently linked with liver toxicity concerns. Now, investors in both firms are likely reassured by the new phase 3 trial, dubbed Orion-11.
Inclisiran has shown a clean safety profile in earlier phases of clinical trials, “but now we can confirm that, because of the size of the study, it’s very safe and there’s no concerns of liver function or renal function,” CEO Mark Timney said.
Between the placebo and inclisiran arms, liver enzyme changes were similar at 0.5% versus 0.5% for ALT and 0.5% versus 0.2% for AST. As for kidney function, plasma creatinine increases were 3.9% and 2.5%, respectively, The Medicines Company reported. Overall, patients who experienced serious adverse events during treatment were around 22% in both groups, and there was no important difference in categories, either, the company’s chief development officer Peter Wijingaard told FiercePharma.
Ability to lower LDL cholesterol is of course important because high levels have long been linked with high risk of cardiovascular disease. But improving cardiovascular outcomes is arguably more important, especially because Praluent and Repatha have each posted heart-helping results.
Inclisiran has some early data to back its case. In the current trial, investigators noticed a statistically significant difference between placebo and inclisiran in the rates of heart attack (2.7% versus 1.2%) and strokes (1.0% versus 0.2%).
The study wasn’t designed to show CV benefits, Wijingaard acknowledged. But the stats are a good sign for the Orion-4 outcomes trial, which is on track to read out around 2024, and fall in line with what the company's expecting from inclisiran given historic trial evidence in the PCSK9 field.
Even without the outcomes data, though, MedCo believes it’s in good shape. The company's market research has shown “that [physicians and patients] will not wait until we have outcomes data,” Timney said. “The LDL-c lowering is heavily validated marker of outcomes improvement, and we hear phrases like ‘We did not wait for outcomes with Crestor, why would we wait here?’”
A more relevant comparison these days, given payer limitations, would be Repatha and Praluent, which still face some authorization hurdles even after major price cuts. But MedCo thinks inclisiran's twice-yearly dosing—compared with every two weeks or once a month for the existing PCSK9s—can give it a marketing edge.
And it's not just convenience in its favor, either, Timney said. The new med is injected by a healthcare provider, which should help with compliance, too.
It “aligns with when these types of patients visit their physician, and therefore is starting to get these additive benefits such as the ability to control adherence,” Timney said. According to him, up to two-thirds of patients don’t adhere to proven first-line cholesterol treatments after one year.
Inclisiran also works differently from Repatha and Praluent, which are antibodies that directly attack the PCSK9 protein. Inclisiran targets the RNA that eventually makes that protein. MedCo has long touted inclisiran as a potential first-in-class small-interfering RNA (siRNA) drug.
Orion-11 tested inclisiran in patients outside the U.S. with atherosclerotic cardiovascular disease, and it's the first phase 3 to read out. Orion-9 in familial hypercholesterolemia and Orion-10, which focuses on U.S. patients, are expected to report data later this year. Combined, the three studies will form inclisiran’s new drug application package to the FDA by year-end and in Europe early 2020, the company says.
To prepare for a launch, MedCo has started pre-commercialization work that’s “with the same level of robustness that a large pharmaceutical company would exercise,” said Timney, whose resume includes a stint at Merck & Co. as U.S. pharma chief and at Purdue Pharma as CEO.
MedCo already has a small team of medical science liaisons and has account executives in place on the payer side, Timney said.
As Amgen, Regeneron and Sanofi have learned, pricing and payer support could be a major problem to success—after all, that’s why they lowered Repatha’s and Praluent’s prices by 60% recently. Timney wouldn’t give away details on his pricing strategy, but said the MedCo drug will be “positioned very differently” on the market because it “offers a vastly different value proposition compared to any other lipid-lowering therapy.”