Alnylam, The Medicines Company's Long-Acting Cholesterol Drug May Threaten Amgen, Regeneron-Sanofi's Blockbusters

Published: Sep 01, 2015

ALN-PCSsc Achieves Quarterly and Potentially Bi-Annual Subcutaneous Dose Regimen Profile for Effective LDL-C Lowering in Phase 1 Clinical Study

– Investigational First-in-Class PCSK9 Synthesis Inhibitor Achieves up to 83% Maximal and 64% Mean Maximum LDL-C Lowering, Comparable to Published Results with Anti-PCSK9 Monoclonal Antibodies, but with Clinically Significant Reductions in LDL-C Clamped Down for More than 140 Days after Just a Single Dose –

– ALN-PCSsc Generally Well Tolerated with No Clinically Significant Drug-Related Adverse Events to Date –

– Program Lead Transitions from Alnylam to The Medicines Company, who Together Launch “ORION™” Development Program, with Initial Phase 2 Start Planned by End-2015 and Phase 3 Start Expected in 2017; ORION to Include Comparative Study with Anti-PCSK9 Monoclonal Antibodies

– Companies to Host Conference Call Today, Sunday, August 30th, at 9:30 a.m. ET to Discuss Results –

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, and The Medicines Company (Nasdaq:MDCO), a global biopharmaceutical company focusing on saving lives, alleviating suffering and contributing to the economics of healthcare by focusing on the world’s leading acute/intensive care hospitals, announced today positive initial results from their ongoing Phase 1 clinical trial with ALN-PCSsc at ESC Congress 2015 held August 29 – September 2, 2015, in London. ALN-PCSsc is an investigational RNAi therapeutic targeting PCSK9 – a genetically validated protein regulator of LDL receptor metabolism – being developed for the treatment of hypercholesterolemia. In contrast to anti-PCSK9 monoclonal antibodies (MAbs) that bind to PCSK9 in blood, ALN-PCSsc is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver.

“a major scientific breakthrough that happens once every decade or so”

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.

“Our initial Phase 1 results with ALN-PCSsc, a first-in-class investigational PCSK9 synthesis inhibitor, demonstrate robust, dose-dependent, and durable reductions in LDL-C of up to 83%. Remarkably, significant and clamped lowering of LDL-C is achieved for over 140 days after a single dose. At the 300 mg dose – which we believe is optimal, with fully saturating effects on both LDL-C lowering and PCSK9 knockdown – an injection volume of 1.5 mL and possibly lower can be achieved. Accordingly, we believe that these results support a quarterly, and possibly bi-annual, low volume subcutaneous dose regimen for further development,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. “Importantly, ALN-PCSsc was generally well tolerated with no clinically drug-related significant adverse events to date. Based on these positive results, we believe that ALN-PCSsc potentially represents an innovative, differentiated, and well validated approach for the treatment of hypercholesterolemia. We very much look forward to our continued partnership with The Medicines Company as they now take the lead in developing ALN-PCSsc in the ORION program.”

“Based on these initial Phase 1 results, we believe that ALN-PCSsc has a highly competitive profile as compared with anti-PCSK9 monoclonal antibodies that are labeled for twice-monthly dosing. In particular, we believe that a maximally efficacious and well tolerated quarterly or potentially bi-annual, low volume subcutaneous dosing regimen could address the unmet needs for hypercholesterolemia management in a massive, at-risk, often non-adherent population worldwide. Moreover, we imagine that ALN-PCSsc has the potential to open new innovation horizons with patients, providers, and payers by linking the temporal cycle of LDL-C monitoring with administration of therapy,” said David Kallend, MBBS, Vice President and Global Medical Director at The Medicines Company. “We are now initiating our broad-based ORION development program to advance ALN-PCSsc toward approval and the market. We expect to start our initial Phase 2 study by end of this year, and plan to start our Phase 3 registration studies in 2017. In addition, we plan on performing studies directly comparing ALN-PCSsc with anti-PCSK9 MAbs to confirm the important features and potential benefits of this first-in-class investigational PCSK9 synthesis inhibitor.”

“Elevated LDL-C remains a major risk factor for coronary artery disease, and new therapies are needed for patients who are refractory or intolerant to current approaches for management of their LDL-C levels. PCSK9 therapies have now emerged as a new class of drugs for treatment of hypercholesterolemia, and I believe that these agents have the potential to make a meaningful difference for patients,” said John J.P. Kastelein, M.D., Ph.D., Professor of Medicine and Chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam. “I am very encouraged by these initial clinical data with ALN-PCSsc, especially the durability of LDL-C lowering effects. If the safety and efficacy of this novel investigational PCSK9 synthesis inhibitor can be confirmed in larger studies to support approval, it may offer an important treatment option for patients, physicians, and payers.”

The Phase 1 trial of ALN-PCSsc is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose, subcutaneous dose-escalation study. Enrollment in the study has been completed, but the study is ongoing with continued data collection and subject follow up. The study was designed to enroll up to 76 volunteer subjects with elevated baseline LDL-C (= 100 mg/dL), with subjects randomized 3:1, drug: placebo. The study was performed in two phases: a single ascending dose (SAD) phase and a multiple dose (MD) phase. The MD phase also includes subjects both on and off statin co-medication. The primary objective of the Phase 1 study is to evaluate the safety and tolerability of ALN-PCSsc. Secondary objectives include assessment of clinical activity as determined by knockdown of plasma PCSK9 levels and lowering of serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc.

All results are based on data in the database as of August 4, 2015. A total of 69 subjects were enrolled in the study, with a mean baseline LDL-C of 146 mg/dL. A total of 24 subjects were enrolled in five SAD cohorts and received placebo (N=6) or study drug at fixed doses from 25 mg to 800 mg (N=3, per group; N=6 for the 800 mg cohort). A total of 45 subjects were enrolled in six MD cohorts, with subjects receiving: placebo (N=12); four doses of 125 mg once weekly (N=6); two doses of 250 mg once every two weeks (N=6); two doses of 300 mg once every four weeks (N=6); two doses of 300 mg once every four weeks with statin co-medication (N=4); two doses of 500 mg once every four weeks (N=6); and two doses of 500 mg once every four weeks with statin co-medication (N=5).

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. The durable effects of ALN-PCSsc support a once quarterly, and possibly bi-annual, low volume subcutaneous dose regimen for evaluation in further clinical studies. Results are summarized in the table below.

SAD Group

Maximum %
PCSK9
Knockdown

Mean
Maximum %
PCSK9
Knockdown#

Mean %
PCSK9
Knockdown
at Day 140^

Maximum %
LDL-C
Lowering

Mean
Maximum %
LDL-C
Lowering#

Mean %
LDL-C
Lowering at
Day 140^

Placebo (N=6) 38 29 ± 4 N/A 25 19 ± 2 N/A
25 mg (N=3) 60 54 ± 3 14 44 34 ± 5 15
100 mg (N=3) 73 49 ± 16 -4 ± 41 60 43 ± 9 39 ± 1*
300 mg (N=3) 82 78 ± 2***

62 ± 5*

67 53 ± 7 44 ± 1***
500 mg (N=3) 86 76 ± 7*** 66 ± 9 78 55 ± 12* 39 ± 20
800 mg (N=6) 86 82 ± 2*** Ongoing 69 58 ± 4** Ongoing

#For mean maximum knockdown/reduction relative to baseline, p values from pairwise comparisons vs. placebo using ANOVA model
^For mean knockdown/reduction relative to baseline at Day 140, p values from pairwise t-tests vs. baseline
*p less than 0.05
**p less than 0.01
***p less than 0.001

In the MD cohorts, ALN-PCSsc was associated with potent and highly durable knockdown of PCSK9 and lowering of LDL-C, with similar effects to those observed at lower study drug exposure in SAD cohorts. An up to 94% PCSK9 knockdown and an up to 83% LDL-C lowering were observed, including absolute levels of LDL-C as low as 18 mg/dL. The LSM % reduction in LDL-C from baseline at 12 weeks was 59.4% in the 300 mg once-monthly dose cohort. All MD groups showed similar levels of PCSK9 knockdown and reductions in LDL-C, indicating that all doses achieved a fully saturating effect for a PCSK9 synthesis inhibitor with an approximately 80% knockdown of PCSK9 and an approximately 60% LDL-C lowering. Also, PCSK9 knockdown and LDL-C lowering were similar in subjects with or without statin co-administration, suggesting that ALN-PCSsc may be able to substantially reduce LDL-C in individuals already on a statin and not at target levels. Data collection beyond 98 days is ongoing. Results are summarized in the table below.

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