Additional Relevant Details
In the Phase 1 study, subcutaneous administration of ALN-PCSsc resulted in an up to 83% lowering of LDL-C, with an up to 64 ± 5% mean maximum reduction, comparable to published results for anti-PCSK9 MAbs (Zhang XL., et al., BMC Med, 2015). Similar reductions in LDL-C were seen in patients on and off concomitant statin therapy. The effects of ALN-PCSsc were highly durable, with clinically significant and clamped reductions in LDL-C maintained for over 140 days, supportive of a once-quarterly and possibly bi-annual subcutaneous dose regimen. Maximal lowering effects on LDL-C were consistently achieved at a dose of 300 mg associated with a low injection volume of 1.5 mL; this dose was significantly below the 800 mg top dose studied per the Phase 1 protocol. Importantly, ALN-PCSsc was generally well tolerated with no clinically significant drug-related adverse events. The development leadership of ALN-PCSsc now transitions from Alnylam to The Medicines Company, who together announce today initiation of the ORIONTM development program, with an initial Phase 2 study planned to begin by end-2015 and a Phase 3 study expected to begin by end-2017. ORION is also expected to include a comparative study of ALN-PCSsc with anti-PCSK9 MAbs.


In the SAD cohorts, ALN-PCSsc administration was associated with potent, dose-dependent, and highly durable knockdown of PCSK9 and lowering of LDL-C. An up to 86% maximal knockdown of PCSK9 relative to baseline was achieved, with an up to 82 ± 2% mean maximum PCSK9 knockdown (p < 0.001, compared to placebo). Even in the lowest dose group of 25 mg, significant knockdown of PCSK9 was observed. Maximal effects toward PCSK9 were achieved at the 300 mg dose, with further dose escalation yielding minimal additive effects; the volume of drug at the 300 mg dose was 1.5 mL. Knockdown of PCSK9 was highly durable, with a 62 ± 5% mean effect (p < 0.05, compared to baseline) in the 300 mg cohort maintained at 140 days after a single dose.In the SAD cohorts, an up to 78% maximal lowering of LDL-C was achieved, with an up to 58 ± 4% mean maximum LDL-C lowering (p < 0.01, compared to placebo); absolute levels of LDL-C as low as 30 mg/dL were observed. As with PCSK9 knockdown, maximal, fully saturating effects on LDL-C lowering were achieved at the 300 mg dose. Reductions in LDL-C were highly durable, with a 44 ± 1% mean lowering (p < 0.001, relative to baseline) in the 300 mg cohort maintained at 140 days after a single dose; data collection beyond 140 days is ongoing. The least squares mean (LSM) % reduction in LDL-C from baseline at 12 weeks - a measure used in studies of anti-PCSK9 MAbs - was 50.1% in the 300 mg cohort; this is comparable to the 50-60% range of values reported for MAbs, but was achieved after just a single dose.

ALN-PCSsc was found to be generally well tolerated, with no clinically significant drug-related adverse events to date. There were no serious adverse events (SAEs) or drug-related discontinuations. All adverse events (AEs) were mild or moderate in severity. At higher drug exposures of 500 mg or greater, four subjects receiving ALN-PCSsc reported mild, localized injection site reactions (ISRs) that resolved without medical intervention. At or below the lowest maximally effective dose of 300 mg, there were no ISRs noted in any SAD or MD cohort subjects (0/19). One subject in the 500 mg MD group developed alanine transaminase (ALT) elevations approximately 4 times upper limit of normal (ULN) without change in bilirubin, but this was attributed to concomitant statin therapy and improved upon statin discontinuation. There were no clinically significant changes in other laboratory safety measurements, including cytokine levels, or hematologic parameters. There were also no clinically significant changes in renal function tests.