Long-term inclisiran data suggest The Medicines Company/Alnylam drug will flourish in pivotal study, disrupt 'bad' cholesterol market
Ahead of the keenly anticipated pivotal late-stage readout for its Alnylam $ALNY-partnered long-acting cholesterol fighter inclisiran, The Medicines Company on Saturday afternoon unveiled long-term Phase II data that suggested the biannual-dosed drug is as safe and effective as the approved once-monthly Repatha and Praluent.
Unlike Repatha from Amgen $AMGN, as well as Praluent from Regeneron $REGN and Sanofi $SNY — which work by inhibiting the PCSK9 protein and thereby diminishing LDL-C or “bad” cholesterol — inclisiran is a siRNA therapy designed to curb the production of the PCSK9 protein at its source in the liver to oust LDL-C from the bloodstream.
Despite the wide adoption of statins, such as Pfizer’s nearly $13 billion-at-peak Lipitor, hypercholesterolemia and associated cardiovascular disease is endemic in the United States, representing fertile ground for fresh, potent therapies to reap lucrative returns. Repatha and Praluent were first approved in 2015 in post-statin patients amidst much fanfare, but instead faced pushback from insurers for their high sticker prices ($14,000) that led to lower-than-expected adoption. However, since then, trials have demonstrated the PCSK9 inhibitors also significantly cut cardiovascular risk — data that are now reflected on their labels — and their manufacturers have also slashed the prices of their respective drugs by 60%, in a bid to boost tepid sales. So there is “nowhere for inclisiran to hide on either efficacy or safety (especially safety),” Baird analysts wrote in a March initiation note.
Data on Saturday came from ORION-3 — a follow-on trial from the Phase II ORION-1 study. Patients who completed ORION-1 were enrolled in ORION-3, and were divided into two groups. In the first group, subjects (n=290) previously treated with any inclisiran dose in ORION-1 received twice-a-year injections of inclisiran sodium 300 mg. The main goal was the mean percent change in LDL-C from the ORION-1 baseline value, measured at day 210.
Analysts suggested the data bode well for the incoming late-stage inclisiran readout, expected in the third quarter. “These results have increased our conviction in inclisiran ascending the Iron Throne of PCSK9 drugs,” Baird analysts wrote in a note on Sunday. The Medicines Company’s shares were up nearly 9% at $35.95 before the bell on Monday.
In the ORION studies, patients with active liver disease were excluded, which should allow “inclisiran to avoid most of the adverse events seen previously with some GalNAc siRNA drug candidates,” SVB Leerink analysts wrote in a note earlier this month. That prediction proved pertinent. In terms of safety, inclisiran was well tolerated and no material safety issues were observed, The Medicines Company $MDCO said on Saturday.
However, there was a single patient with liver enzyme elevation, and one patient death due to a stroke, which was deemed unrelated to the drug.
“While MDCO bears will cling to the single liver enzyme elevation event observed in ORION-3, several considerations make that argument untenable,” argued Baird analysts. For instance, the patient that experienced the liver enzyme elevation was being treated with Arthrotec for a gout flare-up, they wrote. “Invoking Occam’s Razor, the simplest explanation for the liver enzyme elevation was the drug known for decades to cause liver enzyme elevations.”
Jefferies analysts suggested that overall, the data represented a “clean safety profile…out to 3 years which was one of the key investor questions heading into the PIII readout.”
Data also showed that inclisiran-treated patients experienced a 51% reduction in LDL-C levels through day 210, and time-averaged absolute reductions of 59.4mg/dL for up to 3 years.
Amgen’s Repatha reported LDL-C reduction of 56% at year 3, “in patients with elevated LDL after statin intolerance or max-tolerated statins (so a slightly different group of patients than ORION-3),” Jefferies analysts wrote in a note. “We believe this dosing schedule is attractive to patients and can improve adherence, since currently only 55-60% patients are compliant on PCSK9 Ab therapy.”
Apart from Praluent and Repatha, inclisiran will likely also have to contend with Esperion’s $ESPR LDL drug bempedoic acid — which is under FDA review — although it has not shown to be as effective as the approved PCSK9 drugs.
Meanwhile, patients from ORION-3’s group 2 (n=92) were patients given placebo in ORION-1. They have received one year of treatment with Repatha (140 mg injections every two weeks) followed by three years of treatment with inclisiran sodium 300 mg given on day 360 and 450 and every six months thereafter. Data on these patients are expected sometime in 2022.
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