Clinical Trials

Date: 2017-08-28

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the European Society of Cardiology (ESC) Congress 2017

Company: Alnylam Therapeutics (USA - MA) The Medicines Company (USA - NJ)

Product: inclisiran (ALN-PCSsc)

Action mechanism:

• RNAi/PCSK9 inhibitor. ALN-PCSsc is a subcutaneously administered RNAi therapeutic targeting the gene proprotein convertase subtilisin/kexin type 9 (PCSK9), a target validated by human genetics that is involved in the metabolism of low-density lipoprotein cholesterol (LDL-C, or “bad” cholesterol). This first-in-class investigational medicine acts by turning off PCSK9 synthesis in the liver. Recent pre-clinical results in non-human primate (NHP) studies demonstrated that a single dose of ALN-PCSsc significantly reduced plasma PCSK9 protein by up to 96%, with mean PCSK9 knockdown at nadir of 88% at the top dose. Results also showed lowering of LDL-C of up to 77%, with a mean reduction of 69% at the top dose; these results were observed in the absence of statin co-administration. Knockdown of PCSK9 and lowering of LDL-C were rapid and durable, with maximal effects lasting greater than 90 days and returning to baseline at approximately 160 days. At the top dose of 10 mg/kg, an over 50% reduction in LDL-C was maintained for over 90 days. Moreover, there was sustained and clamped knockdown of PCSK9 and reduction of LDL-C across this entire time period, which contrasts with the cyclical variation in LDL-C observed with monthly dose regimens of anti-PCSK9 monoclonal antibodies (Stein, Curr Opin Lipidol 2013, 24:510–517). All together, these pre-clinical data are supportive of a once-monthly, and possibly once-quarterly, dosing regimen, which could represent a highly competitive target product profile. In addition, four-week GLP toxicology studies evaluating doses administered every other week confirmed that ALN-PCSsc has a wide therapeutic index, with a No Observed Adverse Effect Level (NOAEL) of greater than 250 mg/kg in rats and NHP.
• 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.

Disease: atherosclerotic cardiovascular disease, familial hypercholesterolemia

Therapeutic area: Cardiovascular diseases - Genetic diseases

Country: Canada, Germany, Netherlands, UK, USA

Trial details:

• ORION-1 is a placebo-controlled, double-blind, randomized, dose-finding Phase 2 trial of single or multiple subcutaneous injections of PCSK9si in a total of 501 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 trial compares the effect of different doses of PCSK9si and evaluates the potential for dosing no more than two, three or four times per year. (NCT02597127)

Latest news:

• • On August 28, 2017, The Medicines Company  and Alnylam Pharmaceuticals announced new, positive data from the ORION-1 Phase II study of inclisiran being developed for the treatment of hypercholesterolemia. The data were presented  in the "Hot Line - Late-Breaking Clinical Trials 2" session at the European Society of Cardiology (ESC) Congress 2017, being held in Barcelona, Spain.
• Following the presentation of primary results from ORION-1 at ACC.17 in March 2017 and publication of results in The New England Journal of Medicine in May 2017 (see below), the data presented at ESC 2017 complete an important picture of patient follow-up to one year, including time-averaged LDL-C lowering effects, intra-patient variability and extended safety observations.
• Efficacy data affirm inclisiran's significant LDL-C lowering effects following a starting dose of 300 mg given on Day-1 and Day-90, after which the mean LDL-C reduction was 56% at Day-150 and 51% at Day-180. For the subsequent six-month period - from Day-90 to Day-270 - the time-averaged LDL-C reduction was 51% with minimum intra-patient variability over time (all comparisons to placebo P < 0.0001). These robust data underscore the selection of a six monthly maintenance dose of 300 mg in Phase III trials, which are now in advanced stages of preparation. The Phase III LDL-C lowering trials in 3,500 patients, which are designed to form the basis for inclisiran approval in the United States and Europe, are expected to test the starting dose of 300 mg given on Day-1 and Day-90, followed by a maintenance dose of 300 mg given every six months for up to 18 months.
• With completion of one-year follow-up, safety data for inclisiran from the Phase II ORION-1 study now include 370 subject-years of observation, including at least 300 subject-years of inclisiran effects. As in prior analyses, no material safety issues were observed on inclisiran, which continued to demonstrate an adverse event profile similar to placebo. There were no deaths or serious adverse events during the extended observation period. In particular, in spite of the prolonged LDL-C lowering effects of inclisiran, there were no investigational drug-related elevations of liver enzymes and no neuropathy, change in renal function, thrombocytopenia or anti-drug antibodies during extended follow-up, or at any earlier time periods in the ORION-1 study.
• The extended observation also demonstrated that, after nine months, with no further inclisiran treatment, LDL-C returns towards pre-treatment levels in a near-linear manner. This observation also supports dose planning for further trials. One-year ORION-1 data reaffirm inclisiran's potential to address unmet needs with a highly-differentiated, infrequent, low-volume dosing regimen of two injections per year.
• "With scientific advice and regulatory input from the FDA, the European Medicines Agency (EMA) and others, we have made great progress thoughtfully and aggressively advancing inclisiran into Phase III development and look forward to announcing the initiation of patient recruitment into an LDL-C lowering Phase III program, which we believe will provide the data for New Drug Application and Marketing Authorization Application submissions as early as the second half of 2019" " said Clive Meanwell, Chief Executive Officer of The Medicines Company.
• These trials aim to study 3,000 subjects with atherosclerotic cardiovascular disease (ASCVD) or their risk-equivalents (ORION-10 and -11 trials), 400 subjects with heterozygous familial hypercholesterolemia (ORION-9 trial) and 60 subjects with homozygous familial hypercholesterolemia (ORION-5 trial). The company is also advanced in the design and preparation of a highly-efficient cardiovascular outcomes trial of 15,000 subjects with high risk ASCVD (ORION-4).
• • On March 17, 2017, The Medicines Company and Alnylam Pharmaceuticals reported final results from the ORION-1 Phase II study of inclisiran being developed for the treatment of hypercholesterolemia. The results are being presented today in the "Late-Breaking Clinical Trials - Featured Clinical Research 1" session at the American College of Cardiology's 66th Annual Scientific Session, ACC.17, and have been published in the March 17, 2017 online issue of The New England Journal of Medicine . The detailed data from ORION-1 showed that inclisiran delivered significant and sustained reductions of LDL-C and high standards of safety and tolerability. Every patient who received the two dose starting regimen displayed a significant response and the mean LDL-C reductions over time were practically constant. Inclisiran was well tolerated and no material safety issue was observed, including no investigational drug-related elevation of liver enzymes and no neuropathy, change in renal function, thrombocytopenia, or anti-drug antibodies.
• In ORION-1, the mean baseline LDL-C was approximately 130 mg/dL among 497 randomized and treated patients. The optimal starting dose regimen (300 mg injection administered on Day-1 and Day-90) achieved a mean LDL-C reduction of 52.6% and up to 81% at Day-180, and a time-adjusted mean of > 50% for the six month period from Day-90 through Day-270. For all dose groups, at all time points, differences in the primary (LDL-C) and secondary (PCSK9) endpoints between inclisiran and placebo were statistically significant.
• The overall incidence of treatment emergent adverse events was 76% in both patients randomized to placebo and patients randomized to inclisiran, with no significant difference between inclisiran doses. Injection site reactions associated with inclisiran were infrequent (observed in 6.5% of patients given the two dose starting regimen and 3.8% of patients given the one dose starting regimen), mild or moderate, and transient.
• • On November 15, 2016, The Medicines Company and Alnylam Pharmaceuticals announced positive results from the analysis of Day 90 data for 497 patients, as well as analysis of preliminary Day 180 data for 189 patients, enrolled in the ORION -1 Phase 2 study of inclisiran. Data from ORION-1 were presented in a Late-Breaking Clinical Trials session at the American Heart Association Scientific Sessions 2016 in New Orleans.
• Inclisiran was generally well tolerated and no material safety issue was observed, including no elevations of liver enzymes considered related to study medication and no neuropathy or change in renal function. Overall incidence of treatment emergent adverse events was 54% both in patients randomized to placebo and in patients randomized to inclisiran, with no differences between inclisiran doses. Injection site reactions with inclisiran were infrequent (observed in 3.2% of patients), mild or moderate, and transient - in only 2.4% of patients, the reported injection site reaction started or was still present 4 or more hours after dosing.
• Baseline LDL-C was approximately 130 mg/dL among 497 randomized and treated patients. Among these patients, one 300 mg subcutaneous injection of inclisiran achieved mean LDL-C reductions of 51% at Day 60, which were durable to Day 90 (mean 45% and up to 76%). All differences relative to placebo in these 497 patients were statistically significant.
• Among 189 randomized and treated patients who had been followed for 180 days or more by the interim data cut-off date of October 25, 2016, one 300 mg subcutaneous injection of inclisiran achieved mean LDL-C reductions of 59% at Day 60, which were durable to Day 90 (mean 50%) and Day 180 (mean 43% and up to 81%). Two 300 mg injections of inclisiran - one given on Day 1 and one on Day 90 - achieved a mean LDL-C reduction of 57% at Day 120, which was durable to Day 180 (mean 52% and up to 81%). All differences relative to placebo in these 189 patients were statistically significant.
• • On October 18, 2016, The Medicines Company 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.
• 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.
• • On January 11, 2016, The Medicines Company  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  or risk equivalent ASCVD and elevated LDL-C.

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