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The Medicines Company, Inc.

Partner : Alnylam

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The Medicines Company Announces Positive Top-Line Results from Day 180 Interim Analysis in Ongoing ORION-1 Phase 2 Study of Inclisiran (formerly, PCSK9si)

Compelling safety and efficacy data from Day 180 interim analysis

Inclisiran continued to demonstrate significant and durable LDL-C reduction, reaffirming the potential for a highly-differentiated dosing regimen of two or three injections per year

Inclisiran continued to demonstrate high standards of safety and tolerability

The Medicines Company reinforces its commitment to advancing the development of inclisiran with initiation of ORION-2 study (homozygous familial hypercholesterolemia) and ORION-3 study (open-label, active comparator extension study for patients completing ORION-1)

PARSIPPANY, N.J.--(BUSINESS WIRE)--Jan. 8, 2017-- The Medicines Company (Nasdaq:MDCO) today announced positive top-line results from the interim analysis with Day 180 follow-up for all 501 patients enrolled in the ongoing ORION-1 Phase 2 study of inclisiran, its investigational, first-in-class PCSK9 synthesis inhibitor. In the interim analysis, inclisiran continued to demonstrate significant and durable LDL-C reduction, reaffirming the potential for a highly-differentiated, low-volume dosing regimen of two or three injections per year. Inclisiran was well tolerated and no material safety issue, including no investigational drug-related elevation of liver enzymes, neuropathy or change in renal function, was observed. Injection site reactions with inclisiran were infrequent, mild or moderate, and transient.

"Once again, we are highly encouraged by the strength and consistency of the safety and efficacy data from ORION-1, which reaffirm our confidence in the great potential of inclisiran and reinforce our decision to accelerate the development of this highly-differentiated and potentially transformational approach to treating patients with hypercholesterolemia,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “We continue to focus our resources on thoughtfully and aggressively advancing inclisiran into Phase 3 development to ensure that this promising new treatment option is made broadly available to the millions of at-risk, often non-adherent, patients worldwide who continue to struggle with high cholesterol using available therapies. Our initiation of the ORION-2 study and enrollment of ORION-1 patients into the ORION-3 extension study, both of which we announced today, demonstrate our strong commitment to these patients.”

The complete follow-up data for all 501 patients to Day 210 (completion of the ORION-1 study), including Day 180 efficacy data, has been submitted for presentation at the American College of Cardiology’s 66th Annual Scientific Session, to be held March 17 – 19, 2017, in Washington, DC. In order to protect the scientific integrity of the ongoing ORION-1 study, the Company does not expect to provide additional information or make further public statements regarding the results of the study until such time as the data is presented. The Medicines Company also expects to engage in discussions with regulatory authorities regarding the Company’s Phase 3 development plan for inclisiran prior to the initiation of its pivotal clinical trial, ORION-4.

Initiation of ORION-2 Study

The Medicines Company also announced today that it has initiated the ORION-2 study of inclisiran in patients with Homozygous Familial Hypercholesterolemia (HoFH). The study will examine the efficacy, safety and tolerability of inclisiran in patients with HoFH.

Initiation of ORION-3 Study

The Medicines Company also announced today that it has initiated ORION-3, a Phase 2, open-label extension study, with an active comparator (evolocumab), for patients completing the ongoing ORION-1 study. The ORION-3 study will evaluate the efficacy, safety and tolerability of long-term dosing of inclisiran and will also measure the effects of treatment, including a comparison of the effects of inclisiran and evolocumab, as well as switching from evolocumab to inclisiran, on certain clinical and patient-reported endpoints. Patients completing ORION-1 will receive inclisiran or evolocumab, based on the treatment received in ORION-1. Those patients who received inclisiran will receive inclisiran throughout the ORION-3 study. Those patients who received placebo will receive evolocumab as comparator for one year, and then switch to inclisiran for the remainder of the ORION-3 study. The estimated study period for ORION-3 is four years, or until inclisiran receives regulatory approval, whichever occurs first. Subject to discussions with regulatory authorities, the ORION-3 study will be conducted in parallel with the Phase 3 development program for inclisiran.
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Source: press release, 1/08/17. http://www.themedicinescompany.com/investors/news/medicines-company-anno...

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The Medicines Company Announces Positive Top-Line Results from Day 90 Interim Analysis in Ongoing ORION-1 Phase 2 Study of PCSK9si

18 Oct 2016
— Compelling efficacy and safety data from ORION-1 interim analysis confirm results up to Day 90 from PCSK9si Phase 1 study and significantly exceed ORION-1 study objectives —

— PCSK9si again demonstrated significant and durable LDL-C reduction-with even greater statistical robustness-reaffirming triannual and potentially biannual dosing regimen —

— PCSK9si continues to demonstrate high standards of safety and tolerability—

— Data from ORION-1 affirm PCSK9si’s highly-competitive profile —

— Detailed results, including Day 90 follow-up for all 501 patients and top-line data from preliminary analysis of Day 180 follow-up for up to 200 patients, will be presented in Late-Breaking Clinical Trial Session at American Heart Association meeting on November 15, 2016 —

PARSIPPANY, N.J.--(BUSINESS WIRE)--Oct. 18, 2016-- The Medicines Company (NASDAQ:MDCO) today announced top-line results from the interim analysis with Day 90 follow-up for all 501 patients enrolled in the ongoing ORION-1 study of PCSK9si, its investigational first-in-class PCSK9 synthesis inhibitor. Data from the interim analysis confirm the significant and durable LDL-C reduction demonstrated up to Day 90 in the preceding Phase 1 study. PCSK9si was well tolerated and no material safety issue was observed in the Day 90 interim analysis of unblinded safety data, including no investigational drug-related elevation of liver enzymes, neuropathy or change in renal function. Injection site reactions were infrequent, mild or moderate, and short-lived.

“We are highly encouraged by the strength and consistency of the Day 90 efficacy and safety data from ORION-1, which build significantly on the promise generated by the preceding Phase 1 study of PCSK9si,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “These compelling interim data affirm PCSK9si’s highly-competitive profile and validate PCSK9si’s game-changing potential. We look forward to presenting results from the ORION-1 study, including Day 180 follow-up for up to 200 patients, at the AHA meeting on November 15, 2016.”

David Kallend, MBBS, Vice President and Global Medical Director at The Medicines Company, added, “Based on the results from our ORION-1 Day 90 interim analysis, PCSK9si has again demonstrated robust and durable knockdown of LDL-C, as well as impressive safety and tolerability. These results validate a triannual, and potentially biannual, low volume subcutaneous dose regimen, which we believe represents a compelling, highly-differentiated approach for treating patients with hypercholesterolemia.”

“The thoughtful and robust design of the ORION-1 study has delivered highly impressive interim data,” 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 of the University of Amsterdam. “The potential for management of hypercholesterolemia with two or three low volume injections per year could open a new, transformative and affordable pathway for patients and physicians in the treatment of atherosclerotic cardiovascular disease.”

The interim analysis of Day 90 follow-up for all 501 patients, as well as top-line data from Day 180 follow-up for up to 200 patients, will be presented in a Late-Breaking Clinical Trials session at the AHA Scientific Sessions 2016 on November 15, 2016 in New Orleans. In order to protect the scientific integrity of the ongoing ORION-1 study, the Company does not expect to provide additional information or make further public statements regarding the results of the study in advance of the ORION-1 presentation at the AHA Scientific Sessions. The Company anticipates that data from Day 180 follow-up in all 501 patients will be completed, analyzed and top-line results disclosed before the end of 2016.
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Source: press releae, 10/18/16. http://www.themedicinescompany.com/investors/news/medicines-company-anno...

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The Medicines Company Provides Progress Update on Ongoing ORION-1 Study of PCSK9si

5 Oct 2016
—Results from ORION-1 interim analysis with Day 90 follow-up will be presented in Late-Breaking Clinical Trial Session at American Heart Association (AHA) meeting on November 15, 2016—

—The Company anticipates that top-line data from Day 180 follow-up for up to 200 patients will also be presented at the Late-Breaking Clinical Trial Session—

—Based on review of safety data by the Independent Data Monitoring Committee through August 26, 2016 (unblinded) and the Company through September 29, 2016 (blinded), no material safety issue and, in particular, no drug-related neuropathy, elevation of liver enzymes or changes in renal function, has been observed—

PARSIPPANY, N.J.--(BUSINESS WIRE)--Oct. 5, 2016-- The Medicines Company (NASDAQ:MDCO) today provided a progress update on the ongoing ORION-1 study of PCSK9si, its investigational first-in-class PCSK9 synthesis inhibitor.

ORION-1 is a placebo-controlled, double-blind, randomized Phase II trial of single or multiple subcutaneous injections of PCSK9si in patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (e.g., diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated doses of LDL-C lowering therapies. The study compares the effect of different doses of PCSK9si and evaluates the potential for a quarterly or bi-annual dosing regimen. The primary endpoint of the study is the percentage change in LDL-C from baseline at Day 180. The study exceeded its enrollment target of 480 patients ahead of schedule, enrolling a total of 501 patients between January 21, 2016 and June 2, 2016.

An interim analysis of Day 90 follow-up for all 501 patients will be conducted and presented in the Late-Breaking Clinical Trial Session at the AHA Scientific Sessions 2016 on November 15, 2016 in New Orleans. In addition, the Company anticipates that top-line data from Day 180 follow-up for up to 200 patients will be presented at the Late-Breaking Clinical Trial Session and Day 180 follow-up in all 501 patients will be completed, analyzed and top-line results disclosed before the end of 2016.

Safety data from the ORION-1 study is subject to regular, detailed review and assessment by the Independent Data Monitoring Committee (IDMC). The IDMC has raised no safety concerns and made no safety-related study recommendations through its most recent review on August 26, 2016. Moreover, based upon the Company’s review of blinded safety data through September 29, 2016, the most recent date for which safety data has been made available, no material safety issue and, in particular, no drug-related neuropathy, elevation of liver enzymes or changes in renal function, has been observed. At that date, the 501 study patients had treatment exposure of between 4 and 8 months.

“These impressive, emerging safety data support our view that PCSK9si has a highly-competitive profile as compared with anti-PCSK antibodies and we look forward to presenting results from the ORION-1 study at the AHA meeting on November 15, 2016,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “In particular, we believe that PCSK9si has the unique potential to provide new, innovative solutions to patients, payers and providers through a quarterly or, potentially, bi-annual, low-volume subcutaneous dosing regime and by linking the LDL-C monitoring cycle with administration of therapy.”
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Source: press release, 10/05/16. http://www.themedicinescompany.com/investors/news/medicines-company-prov...

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The Medicines Company Completes Patient Enrollment for ORION-1 Study of PCSK9si

2 Jun 2016
Phase II study enrolled ahead of schedule
Randomized 501 patients with high cardiovascular risk and high LDL-C (“bad cholesterol”) despite current treatment
Aim to demonstrate LDL-C lowering for six months following single-dose treatment
Treatment results anticipated by year-end 2016

PARSIPPANY, N.J.--(BUSINESS WIRE)--Jun. 2, 2016-- The Medicines Company (NASDAQ:MDCO) has announced the completion of patient enrollment in the ORION-1 study of PCSK9si, its investigational first-in-class RNA interference (RNAi) proprotein convertase subtilisin/kexin type 9 synthesis inhibitor (PCSK9si).

The study – which started enrolling in January 2016 – met its target of enrolling 480 patients with high cardiovascular risk and elevated LDL-C ahead of schedule. Follow-up of these patients will track the effects of different dosages of PCSK9si on LDL-C. A previous study showed that a single dose of PCSK9si lowered LDL-C significantly for six months - supporting the potential for subcutaneous dosing as infrequently as twice a year. Experts believe that such a dosing schedule could significantly improve patient adherence to treatment. Patient adherence to current treatments for elevated levels of bad cholesterol is recognized as a major problem in cardiovascular health management.

Interim three-month and six-month effectiveness and safety data from patients in ORION-1 are expected to be available, analyzed and presented by the end of 2016.

“We and our partners at Alnylam are pleased to have completed enrollment of ORION-1. We believe that PCSK9si has significant potential given its highly competitive profile as compared with anti-PCSK9 monoclonal antibodies (MAbs), a recently approved class of LDL-C lowering drugs. Indeed, in our view, the potential for management of hypercholesterolemia with two injections per year could be a transformative option for patients, physicians, and payers in the treatment of atherosclerotic cardiovascular disease (ASCVD),” said David Kallend, MBBS, Vice President and Global Medical Director, The Medicines Company. “Assuming positive data from ORION-1, we are on track to initiate Phase 3 registration studies in early 2017. In addition, we plan on conducting studies directly comparing PCSK9si with anti-PCSK9 MAbs as well as studies in homozygous familial hypercholesterolemia starting this year, to confirm the important features and potential benefits of this first-in-class investigational PCSK9 synthesis inhibitor.”
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Source: press release, 6/02/16. http://www.themedicinescompany.com/investors/news/medicines-company-comp...

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Clive A. Meanwell, Chairman and CEO, gave guidance for data from the phase-II ORION-1 study. He stated, "We believe that the data support twice-yearly dosing, which we and experts in the field believe could be a class-leading attribute. The phase-II study in question ORION-1 is a placebo-controlled, double-blind randomized trial and up to 480 subjects testing the efficacy, safety, and durability of a range of doses. The trial is being run at approximately 54 centers in the Netherlands, Canada, Germany, the United States, and the United Kingdom. Patients will be evaluated for LDL-C lowering effect on day 90 in an interim analysis and the primary endpoint measurement is at 180 days. Further details of the trial are posted on ClinicalTrials.gov. We expect to complete and report results during the fourth quarter 2016, and in addition during 2016, we expect to initiate a randomized trial of this compound in homozygous familial hypercholesterolemia called ORION-2."
Source: Q4 2015 earnings conference call, 2/17/16.

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ALN-PCSsc: Announced positive results from the Phase 1 study of ALN-PCSsc at the American Heart Association 2015 Scientific Sessions demonstrating the drug’s durable effects on PCSK9 knockdown and LDL-cholesterol reduction. Launched patient enrollment in the Orion-1 Phase 2 clinical trial of ALN-PCSsc in patients with atherosclerotic cardiovascular disease
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Source: press release, 2/17/16. http://www.themedicinescompany.com/investors/news/medicines-company-repo...

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The Medicines Company Advances Clinical Development of Investigational First-in-Class PCSK9 Synthesis Inhibitor for Atherosclerotic Cardiovascular Disease (ASCVD)

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11 Jan 2016
Initiates sites and begins enrolling patients in dose-finding Phase 2 study

Study will evaluate effectiveness of ALN-PCSsc on LDL-C levels with quarterly and bi-annual dosing regimens to determine dose and dose regimen for anticipated Phase III

PARSIPPANY, NJ--(BUSINESS WIRE)--Jan. 11, 2016-- The Medicines Company (NASDAQ:MDCO) today announced that it has initiated study sites and begun enrolling patients in the ORION-1 Phase 2 study to compare the effect of different doses of ALN-PCSsc given as subcutaneous injections in a quarterly or bi-annual dosing regimen in subjects with atherosclerotic cardiovascular disease (ASCVD) or risk equivalent ASCVD and elevated LDL-C. ALN-PCSsc is an investigational RNA interference (RNAi) therapeutic targeting PCSK9 – a genetically validated protein regulator of LDL receptor metabolism. 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.

The ORION-1 study is a Phase 2, placebo-controlled, double-blind, randomized trial in 480 subjects with atherosclerotic cardiovascular disease or ASCVD-risk equivalents (e.g., diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated doses of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of ALN-PCSsc injection(s).

“The results from the Phase 1 study of ALN-PCSsc were impressive, and we are excited to see the rapid progression of this therapy into the next phase of its development,” said John J.P. Kastelein, MD, PhD, Professor of Medicine, Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam and Chairman of the Executive Committee for ORION-1. “We look forward to the expected completion of this Phase 2 trial by the end of 2016 to confirm what may be an advantageous dosing regimen for patients at risk for cardiovascular events due to elevated LDL-C.”

“We are very pleased with the rapid development progress for ALN-PCSsc, which has moved from Phase 1 to Phase 2 in a few weeks,” said Clive Meanwell, MD, PhD, Chief Executive Officer, The Medicines Company. “We remain very excited about the prospects of having a bi-annual dosing treatment available for LDL-C reduction which has the potential to improve adherence and address a major unmet medical need.”

“We are pleased to have successfully completed the transition of ALN-PCSsc to our partners at The Medicines Company,” said John Maraganore, PhD, Chief Executive Officer of Alnylam Pharmaceuticals, Inc. “Given our world-leading expertise in RNAi therapeutics, we look forward to providing all necessary support to enable MDCO efforts, including in areas such as regulatory and manufacturing.”

The Medicines Company and Alnylam Pharmaceuticals are collaborating in the advancement of ALN-PCSsc per the companies’ agreement formed in early 2013. Under the terms of the agreement, Alnylam completed certain pre-clinical studies and the Phase 1 clinical study, with The Medicines Company leading and funding the development of ALN-PCSsc from Phase 2 forward as well as potential commercialization.
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Source: press release, 1/11/16. http://www.themedicinescompany.com/investors/news/medicines-company-adva...

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Orion-1 - A Placebo-controlled, Double-blind, Randomized Trial to Compare the Effect of Different Doses of ALN-PCSSC Given as Single or Multiple Subcutaneous Injections in Subjects With High Cardiovascular Risk and Elevated LDL-C
Enrollment: 501
Study Start Date: January 2016
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. https://clinicaltrials.gov/ct2/show/NCT02597127?term=ALN-PCSsc&rank=2

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Inclisiran (ALN-PCSsc)CardiovascularHypercholesterolemiaRNAi therapeuticPCSK9

Mechanism of action: Inclisiran (ALN-PCSsc) is an RNAi therapeutic designed to target proprotein convertase subtilisin/kexin type 9, or PCSK9, for the treatment of severe hypercholesterolemia. PCSK9 is a key regulator of LDL receptor levels.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2017-03-17 - 2017-03-19

Results: Pending