Clinical Trials

Date: 2016-11-13

Type of information: Publication of results in a medical journal

phase: 1

Announcement: publication of results in The New English Journal of Medicine

Company: Alnylam Pharmaceuticals (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.
Alnylam and The Medicines Company are collaborating in the advancement of ALN-PCSsc per the companies’ agreement formed in early 2013. The lead development responsibility for inclisiran transitioned from Alnylam to The Medicines Company in August 2015. The two companies are now working to advance inclisiran in the ORION development program, a comprehensive global clinical development plan designed to support regulatory approval and market access worldwide. Inclisiran is currently being studied in the ORION-1 Phase 2 study by The Medicines Company.

Disease: hypercholesterolemia

Therapeutic area: Cardiovascular diseases - Metabolic diseases

Country: UK

Trial details:

The Phase 1 trial of inclisiran was conducted in the U.K. as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose, subcutaneous dose-escalation study. The study enrolled 69 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 included subjects both on and off stable doses of statin co-medication. The primary objective of the Phase 1 study was to evaluate the safety, side effect profile, and pharmacodynamics effects of inclisiran.

Latest news:

• On November 13, 2016, Alnylam Pharmaceuticals and The Medicines Company announced that results from the Phase 1 study of inclisiran, the recommended International Nonproprietary Name (INN) for ALN-PCSsc, were published in The New England Journal of Medicine (NEJM). Results from the study showed doses ?300 mg (single or multiple doses) significantly reduced PCSK9 and LDL cholesterol for at least 6 months. Moreover, inclisiran was found to be generally well tolerated. The NEJM publication highlights key results from the Phase 1 clinical trial of inclisiran, including safety and pharmacodynamic measures (PCSK9, LDL cholesterol, exploratory lipid parameters). In the single-ascending-dose (SAD) phase, pharmacodynamic measures showed:
Doses ?300 mg reduced PCSK9 at day 84 (up to a least-squares mean (LSM) reduction of 74.5%); Doses ?100 mg reduced LDL cholesterol at day 84 (up to a LSM reduction of 50.6%); Reductions in PCSK9 and LDL cholesterol were maintained at day 180 with little variation over the 6-month period for doses ?300 mg. In the multiple-dose (MD) phase, pharmacodynamic measures showed:
Reduced PCSK9 (up to a LSM reduction of 83.8%) and LDL cholesterol (up to a LSM reduction of 59.7%) at day 84; Levels of PCSK9 and LDL cholesterol remained reduced in all the inclisiran cohorts at day 196. Safety and side effect profile evaluations showed: Inclisiran was generally well tolerated following single and multiple subcutaneous dose administration; No serious adverse events (SAEs) or discontinuations due to AEs were reported; All observed adverse events (AEs) were mild or moderate in severity; There was one Grade 3 GGT elevation considered related to statin therapy.
• On November 11, 2015, Alnylam Pharmaceuticals and The Medicines Company reported positive results from their ongoing Phase 1 clinical trial with ALN-PCSsc in a late-breaking oral presentation at the American Heart Association (AHA) Scientific Sessions 2015. As reported previously, subcutaneous administration of ALN-PCSsc resulted in an up to 83 percent lowering of LDL-C, with an up to 64 ± 5 percent mean maximum reduction, comparable to published results for anti-PCSK9 MAbs (Zhang XL., et al., BMC Med, 2015). In new results, the effects of ALN-PCSsc were found to be highly durable, with clinically significant and clamped reductions in LDL-C, supportive of a potential bi-annual subcutaneous dose regimen. Specifically, an up to 53 percent maximal and 47 percent least squares mean reduction in LDL-C was achieved at day 180 after just a single, low volume injection. In addition, ALN-PCSsc was shown to reduce a number of atherogenic lipids, including lipoprotein (a) – or “Lp(a)” – and total cholesterol, which are associated with increased risk of cardiovascular disease. ALN-PCSsc was generally well tolerated with no clinically significant drug-related adverse events.
All data reported were as of data transfer September 24, 2015. Specifically, results from the single ascending dose cohorts (n=24) showed:
Maximal PCSK9 knockdown of 89 percent with mean maximum knockdown of up to 82.3 ± 2.0 percent;
Maximal LDL-C reduction of 78 percent with mean maximum lowering of up to 59.3 ± 5.0 percent;
Maximum reductions of Lp(a) of 77 percent, total cholesterol of 48 percent, apolipoprotein B of 72 percent, and non-HDL cholesterol of 68 percent, with no significant change in HDL cholesterol;
At day 180, an up to 53 percent reduction in LDL-C, with a least squares mean percent lowering of 47.0 percent in the 300 mg dose cohort.
Results from the multiple dose cohorts (n=45) showed:
Maximal PCSK9 knockdown of 94 percent with mean maximum knockdown of up to 88.5 ± 1.6 percent;
Maximal LDL-C reduction of 83 percent with mean maximum lowering of up to 64.4 ± 5.4 percent;
Maximum reductions of Lp(a) of 76 percent, total cholesterol of 55 percent, apolipoprotein B of 68 percent, and non-HDL cholesterol of 73 percent, with no significant change in HDL cholesterol;
At day 208 – approximately 6 months after the last dose – an up to 60 percent reduction in LDL-C, with a least squares mean percent lowering of 44.4 percent in the 300 mg dose cohort;
Similar effects were observed in subjects with and without concomitant statin therapy.
ALN-PCSsc was generally well tolerated following single and multiple subcutaneous dose administration, with no serious adverse events (SAEs) or discontinuations due to AEs. All observed adverse events (AEs) were mild or moderate in severity, and were generally similar in subjects with and without concomitant statin administration. At the higher drug exposures, four subjects experienced mild, localized, and self-limiting injection site reactions (ISRs). One subject developed an approximately four times upper limit of normal increase in alanine transaminase (ALT), without increase in bilirubin that was attributed to concomitant statin therapy; ALT levels resolved upon statin discontinuation and were found to be elevated a second time after re-challenge with a lower dose of the same statin.
• On August 30, 2015, Alnylam Pharmaceuticals and The Medicines Company announced 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. In the Phase 1 study, subcutaneous administration of this RNAi therapeutic targeting PCSK9 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.
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.
• On December 11, 2014, Alnylam and The Medicines Company announced that Alnylam has initiated a Phase 1 clinical trial with ALN-PCSsc, an investigational agent for the treatment of hypercholesterolemia. The initiation of this trial has triggered a $10 million milestone from The Medicines Company to Alnylam. 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 study, enrolling up to 76 volunteer subjects with elevated baseline LDL-C (? 100 mg/dL). As previously guided, the companies expect to report initial clinical data from the trial in mid-2015.
• On November 17, 2014, Alnylam Pharmaceuticals announced that the company has received approval for a Clinical Trial Application (CTA) for ALN-PCSsc, and now expects to start the Phase 1 trial before year’s end with initial clinical data expected in mid-2015.
• On October 28, 2014, Alnylam Pharmaceuticals and The Medicines Company announced that Alnylam has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency to initiate a Phase 1 clinical trial with ALN-PCSsc, an investigational agent for the treatment of hypercholesterolemia. Per the filed CTA, the Phase 1 trial of ALN-PCSsc will be conducted in the UK as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose study, enrolling up to 76 volunteer subjects with elevated baseline LDL-C (? 100 mg/dL). Following approval of the CTA, the companies expect to initiate dosing in the Phase 1 trial in late 2014 or early 2015, with initial data expected to be reported in mid-2015.Alnylam and collaborators previously published complete study results from a Phase 1 trial with ALN-PCS02 in The Lancet (Fitzgerald, et al., The Lancet, doi:10.1016/S0140-6736(13)61914-5). The paper showed that ALN-PCS02 administration resulted in rapid, dose-dependent knockdown of plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of LDL-C of up to 57% relative to baseline and placebo. The knockdown of PCSK9 and lowering of LDL-C were also found to be durable, with effects lasting for weeks after a single dose. ALN-PCS02 was shown to be well tolerated in this Phase 1 study and there were no serious adverse events related to study drug administration.
As per the filed CTA, the Phase 1 trial of ALN-PCSsc will be conducted as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose, subcutaneous dose-escalation study. The study is 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 will be performed in two phases: a single ascending dose (SAD) phase and a multi-dose phase. In the multi-dose phase, subjects will receive two subcutaneous doses of either ALN-PCSsc or placebo administered four weeks apart; the multi-dose phase will also include 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 serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc.

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