Aug 30, 2015 Press Release for Alnylam

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

Aug 30, 2015

- 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.

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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 ORION^TM 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.

MD Group

Maximum % PCSK9 Knockdown

Mean Maximum % PCSK9 Knockdown#

Maximum % LDL-C Lowering

Mean Maximum % LDL-C Lowering#

Placebo (N=11)^

63

29 ± 6

43

22 ± 3

125 mg qW x4 (N=6)

86

82 ± 1***

60

51 ± 2

250 mg q2W x2 (N=6)

85

81 ± 1***

70

60 ± 5***

300 mg qM x2 (N=6)

87

79 ± 3***

79

64 ± 5***

300 mg qM x2 w/ statin (N=3)^

88

86 ± 1***

69

52 ± 10

500 mg qM x2 (N=6)

86

81 ± 2***

69

55 ± 7**

500 mg qM x2 w/ statin (N=5)

94

88 ± 2***

83

60 ± 8***

^#For mean maximum knockdown/reduction relative to baseline, p values from pairwise comparisons vs. placebo using ANOVA model
*p less than 0.05
**p less than 0.01
***p less than 0.001
^{^}One subject in the placebo group received only a single dose; one subject in the 300 mg qM x2 with statin group received a single dose and discontinued at day 14 due to incarceration; both were excluded

Additional Phase 1 clinical activity results - including further durability data for PCSK9 knockdown and LDL-C lowering effects, as well as changes in exploratory biomarkers such as total cholesterol, apoB, non-HDL-C, and Lp(a) - are planned to be presented at a future date.

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.

The lead development responsibility for ALN-PCSsc will now transition from Alnylam to The Medicines Company, who together will be advancing ALN-PCSsc in the ORION development program, a comprehensive global clinical development plan designed to support ALN-PCSsc regulatory approval and market access worldwide. ORION will begin with an initial Phase 2 study that is expected to start by end of 2015. Further, the companies expect that Phase 3 clinical trials will begin in 2017, and that ORION will include a comparative study of ALN-PCSsc with anti-PCSK9 MAbs.

Alnylam and The Medicines Company are collaborating in the advancement of ALN-PCSsc per the companies' agreement formed in early 2013. Under the terms of the agreement, Alnylam will complete certain pre-clinical studies and a Phase 1 clinical study of ALN-PCSsc and The Medicines Company is responsible for leading and funding development from Phase 2 forward as well as potential commercialization.

Conference Call Information

Alnylam and The Medicines Company will host a conference call today, Sunday, August 30, at 9:30 a.m. ET to discuss these initial Phase 1 results with ALN-PCSsc and the ORION development program. A slide presentation will also be available on the Investors page of the Alnylam website, www.alnylam.com, and on The Medicines Company website, www.themedicinescompany.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 18857833. A replay of the call will be available beginning at 12:30 p.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 18857833.

About Hypercholesterolemia

Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving adequate LDL-C levels with currently available therapies including statins, including genetic familial hypercholesterolemia (FH) patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe forms of hypercholesterolemia are estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with hypercholesterolemia whose disease is inadequately managed by existing therapies.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This ESC-GalNAc-conjugate delivery platform is being employed in nearly all of Alnylam's pipeline programs, including ALN-PCSsc and several other programs in clinical development.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information about Alnylam's pipeline of investigational RNAi therapeutics, please visit www.alnylam.com.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-PCSsc for the treatment of hypercholesterolemia and the potential clinical activity and durability of ALN-PCSsc, expectations regarding the initiation of clinical studies, including studies as part of the ORION development program, expectations regarding the continued development of ALN-PCSsc by The Medicines Company, expectations regarding Alnylam's STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-PCSsc, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to manage operating expenses, Alnylam's ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam's dependence on third parties, including The Medicines Company, for development, manufacture, marketing, sales and/or distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation to update any forward-looking statements.

About The Medicines Company

The Medicines Company's purpose is to save lives, alleviate suffering and contribute to the economics of healthcare by focusing on 3000 leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: serious infectious disease care, acute cardiovascular care, and surgery and perioperative care. The company operates in the Americas, Europe and the Middle East, and Asia Pacific regions with global centers today in Parsippany, NJ, USA and Zurich, Switzerland.

The Medicines Company Forward-Looking Statements

Statements contained in this press release about The Medicines Company that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates," "expects," "hopes" and "potential" and similar expressions, are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether ALN-PCSsc will advance in the clinical trials process on a timely basis or at all, whether physicians, patients and other key decision makers will accept clinical trial results, whether the Company will make regulatory submissions for ALN-PCSsc on a timely basis or at all, whether its regulatory submissions will receive approvals from regulatory agencies on a timely basis or at all, the Company's ability to successfully compete with potential competitors which may discover, develop or commercialize competing products more successfully than we do, and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the SEC on August 7, 2015, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.

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Alnylam Pharmaceuticals, Inc.
Michael Mason, 617-551-8327
Vice President, Finance & Treasurer
or
Spectrum
Liz Bryan, 202-955-6222 x2526 (Media)
or
The Medicines Company
Neera Dahiya Ravindran, M.D., 973-290-6044
Vice President, Investor Relations & Strategic Planning
neera.ravindran@themedco.com
or
Bob Laverty, 609-558-5570 (Media)
Vice President, Communications
robert.laverty@themedco.com

Source: Alnylam Pharmaceuticals, Inc.

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