Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as PCSK9 synthesis inhibitor, Inclisiran, Inclisiran Sodium for injection
ALN-PCSSC · 28 trials · 23 indications
To demonstrate the superiority of inclisiran treatment compared to placebo, when initiated before/at discharge, in combination with standard of care (SoC) (statin therapy +/- LLT (Lipid Lowering Therapy) or non-statin treatment in case of documented statin intolerance) on LDL-C reduction at Day 150
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C \[percent change\] at Day 330
Low-density lipoprotein cholesterol is a type of lipoprotein in the blood. Lipoproteins are particles made of lipids(fats) and proteins that carry fats through the bloodstream. Because of their structure, fats can't move through the blood on their own. So, lipoproteins carry fats to various cells in the body.
Percentage change in LDL-C from Baseline (day 1) to Day 150, Inclisiran arm versus Ezetimibe and placebo. There were two estimands of interest in comparing efficacy of inclisiran as monotherapy against that of placebo or ezetimibe that differ on the treatment of interest used for each and the management of intercurrent events as follows: * Monotherapy Estimand: Inclisiran as monotherapy compared to the use of comparator. This estimand uses a hypothetical strategy where participants who permanently discontinued treatment, died or used other LLTs were handled in a hypothetical scenario of what would have happened if the intercurrent event did not happen. * Treatment-policy Estimand: Inclisiran as monotherapy compared to the use of comparator with or without other lipid lowering therapies (LLTs) added. This estimand ignored the use of other LLTs and treatment discontinuation. Deaths (if any) were handled as an unfavorable outcome using a composite variable strategy.
4-Point-Major Adverse Cardiovascular Events (4P-MACE): composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization.
Safety and tolerability: TEAEs, TESAEs (incidence, severity, relationship to study drug and discontinuation due to TEAEs)
Evaluating inclisiran compared to placebo both on top of maximally tolerated statin therapy in reducing total coronary atheroma volume assessed by coronary computed tomography angiography (CCTA) in participants with a diagnosis of non-obstructive coronary artery disease (NOCAD) without previous cardiovascular events.
3P-MACE is a confirmed composite endpoint which includes cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke.
Change in Low Density Lipoprotein Cholesterol (LDL-C) after 270 days of treatment in adults on established lipid lowering medication or who have been recommended lipid lowering therapy by their health care provider but are unable to tolerate treatment, regardless of treatment discontinuation for any reason and regardless of unforeseen change in the concomitant lipid lowering therapy. Multiple imputation is used to impute missing data using a washout model.
Percent change from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) of an "inclisiran first" implementation strategy compared to usual care at Day 330.
Percentage of patients who discontinued statin therapy ≥ 30 days before the end-of-study visit of an "inclisiran first" implementation strategy compared to usual care, for patients in the FAS excluding those with a medical history of statin intolerance.
Percent change from baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Day 330
Percentage of participants achieving Low-Density Lipoprotein Cholesterol (LDL-C) \< 70 mg/dL at Day 330
Superiority of inclisiran compared to placebo in reducing LDL-C from baseline to Day 330
Evaluation of the safety and tolerability of inclisiran, treatment emergent Adverse events and Serious Adverse Events
Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330 (Year 1)
The primary objective of the study is to evaluate the effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C targets at end of study (EOS). Target is \<70 mg/dL for atherosclerotic cardiovascular disease (ASCVD) subjects and \<100 mg/dL for ASCVD risk equivalent subjects. Risk equivalent subjects are defined as either type 2 diabetes, familial hypercholesterolemia or a 10-year risk of a cardiovascular event ≥20% as assessed by the Framingham Risk Score or equivalent; without a medical history of coronary heart disease , cerebrovascular disease or peripheral artery disease.
Safety assessments include adverse events and serious adverse events until the end of study. End of study visit occured at least 90 days following the last inclisiran dose once a decision was made to end the study (either by the subject, investigator or sponsor). For subjects prematurely and permanently discontinued from study treatment, who were not willing to return within the 90 day timeframe, the EOS visit was scheduled as soon as possible, or if decision to discontinue and not return was made at a specific visit, this visit became the EOS visit.
Percentage Change in LDL-C levels from Baseline to Day 150
Defined as time to first occurrence - during the scheduled treatment period - of: * Coronary heart disease (CHD) death; * Myocardial infarction; * Fatal or non-fatal ischemic stroke; or * Urgent coronary revascularization procedure.
Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 540 reported
Assessments performed at Baseline, Day 90, Day 540, time-adjusted percent change at Day 90 reported
Percent change from baseline in LDL-C was calculated to evaluate the effect of inclisiran at Day 180. Difference between different inclisiran dose groups and the placebo group in percentage change in LDL-C levels from baseline to Day 180 were calculated to capture both, the effect of the study drug and the effect of additional medications, mirroring the conditions in clinical practice. An MMRM (Mixed-effect Model with Repeated Measurement) was used as the primary analysis model, with treatment group, visits, interaction between visits and treatment groups, current use of statins or other lipid-modifying therapies as fixed effects, and baseline LDL-C as a continuous covariate.
Percent Change in LDL-C (beta-quantification) from baseline of the ORION-1 Study to Day 210 in ORION-3. A negative percentage score represents a reduction in LDL-C. Change is relative to ORION-1 Baseline, which is defined as the last available record prior to first study drug administration in ORION-1.
Due to the small number of subjects, and the fact that the data are not normally distributed, the data are presented as descriptive statistics with no inferential and limited summary statistics presented.
Percent Change in LDL-C (beta-quantification) from Baseline to Day 180 in MITT Population
Cmax = maximum observed plasma concentration
AUClast = AUC from time zero to the last measurable concentration sampling time
AUCinf = AUC from time zero to infinity
AUC0-24hr = AUC from time zero to 24 hours
Tmax = time to reach maximum plasma concentration
T1/2 = elimination half-life
CL/F = total body clearance
Vz/F = apparent volume of distribution
Pharmacokinetics parameters of inclisiran
Pharmacokinetics parameters of inclisiran
Pharmacokinetics parameters of inclisiran
Pharmacokinetics parameters of inclisiran
Pharmacodynamics effects of inclisiran
Pharmacodynamics effects of inclisiran
Measurement of effect of renal impairment on PK of inclisiran by assessment of Cmax. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Measurement of effect of renal impairment on PK of inclisiran by assessment of time to reach maximum plasma concentration (Tmax) and time for inclisiran to reach half of its initial value (t1/2). Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Measurement of effect of renal impairment on PK of inclisiran by assessment of area under the curve of the plasma concentration (AUC) from time 0 to 24 hours (AUC0-24), from time 0 to 48 hours (AUC0-48), and from time 0 extrapolated to infinity (AUC0-inf). Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Measurement of effect of renal impairment on PK of inclisiran by assessment of CL/F. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Measurement of effect of renal impairment on PK of inclisiran by assessment of apparent volume of distribution (Vd/F) of inclisiran during the terminal elimination phase. Serial blood samples will be collected for the analysis. PK parameters will be determined from the plasma concentration-time profiles using a noncompartmental approach.
Measurement of effect of renal impairment on PK of inclisiran by assessment of Ae of inclisiran. Pooled urine samples will be used for the analysis.
Measurement of effect of renal impairment on PK of inclisiran by assessment of the urinary recovery rate over a specific collection interval (Fe), calculated as 100\*Ae/Dose. Pooled urine samples will be used for the analysis.
Measurement of effect of renal impairment on PK of inclisiran by assessment of CLr, calculated as Ae/AUC0-48 plasma. CLr will be calculated if possible (for example, if the percent of unchanged drug excreted in urine exceeds 20%). Pooled urine samples will be used for the analysis.
| Arm | Type | Description |
|---|---|---|
| Inclisiran sodium 300 mg s.c. + Standard treatment | EXPERIMENTAL | * Inclisiran sodium 300 mg subcutaneous (s.c.) on top of HIS (+/- LLT) or non-statin LLT in statin intolerant participants * KJX839 284 mg / 1.5 mL (Dose: 300 mg) * Pharmaceutical Dosage Form: solution for subcutaneous injection |
| Matching placebo + Standard treatment | PLACEBO_COMPARATOR | * Matching placebo on top of HIS (+/- LLT) or non-statin LLT in statin intolerant participants * KJX839 Placebo / 1.5 mL (Dose: 0 mg) * Pharmaceutical Dosage Form: solution for subcutaneous injection |
| Inclisiran | EXPERIMENTAL | Year 1 - inclisiran sodium subcutaneous injection (given at Days 1, 90, and 270) Day 360 only - placebo subcutaneous injection Year 2 - inclisiran sodium subcutaneous injection (given at Days 450 and 630) |
| Placebo | PLACEBO_COMPARATOR | Year 1 - placebo subcutaneous injection (given at Days 1, 90 and 270) Year 2 - inclisiran sodium subcutaneous injection (given at Days 360, 450, and 630) |
| Inclisiran - Inclisiran | EXPERIMENTAL | Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) s.c administered on Day 1, Day 90, and Day 270, and placebo on Day 180 |
| Placebo- Inclisiran | PLACEBO_COMPARATOR | Placebo on Day 1 and Day 90 and Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) s.c on Day 180 and 270 |
| Ezetimibe | ACTIVE_COMPARATOR | Placebo s.c. and Ezetimibe p.o. |
| Inclisiran sodium 300mg | EXPERIMENTAL | Inclisiran sodium 300 mg in 1.5 mL solution for injection (subcutaneous) in pre-filled syringe. Randomized in a 1:1 ratio with matching placebo |
| Inclisiran sodium | EXPERIMENTAL | Subcutaneous injection |
| Control+ BS | ACTIVE_COMPARATOR | Participants continued to receive their background lipid lowering therapy plus behavioural support (BS). |
| Inclisiran + BS | EXPERIMENTAL | Participants continued to receive their background lipid lowering therapy, plus inclisiran for injection, plus behavioural support. |
| Inclisiran First | EXPERIMENTAL | Inclisiran sodium 300 mg 1.5 ml (equivalent to 284 mg of inclisiran) + usual care |
| Usual Care | NO_INTERVENTION | Treating physicians were recommended to treat patients in accordance with the 2018 ACC/AHA guidelines |
| Inclisiran with Usual Care | EXPERIMENTAL | Inclisiran sodium 300 mg / 1.5 ml (equivalent to 284 mg of inclisiran) |
| inclisiran sodium 300 mg | EXPERIMENTAL | Subcutaneous injection |
| Part 1 - Inclisiran | EXPERIMENTAL | Inclisiran sodium 300 mg subcutaneous (sc) injection (given at Days 1, 90 and 270) |
| Part 1 - Placebo | PLACEBO_COMPARATOR | Placebo sc injection (given at Day 1, 90 and 270) |
| Part 2 - Inclisiran (Total) | EXPERIMENTAL | Inclisiran sodium 300 mg sc injection (given at Days 450 and 630). In addition, participants assigned to placebo in Part 1 received inclisiran sodium 300 mg sc injection on Day 360, while participants assigned to inclisiran in Part 1 received placebo sc injection on Day 360. |
| Part 2 - Inclisiran | EXPERIMENTAL | Participants who received a dose of 300 mg inclisiran sodium for injection administered by SC injection on Day 270, Day 450 and Day 630. In addition, participants who were assigned to the placebo arm in Part 1 will receive a dose of 300 mg inclisiran sodium administered by SC injection on Day 180 after completion of Part 1. |
| Saline Solution | PLACEBO_COMPARATOR | Placebo will be administered as a SC injection of saline solution on Day 1, Day 90, then every 6 months. |
| 300 mg inclisiran sodium | EXPERIMENTAL | Subcutaneous injection |
| 200 mg inclisiran sodium | EXPERIMENTAL | Subcutaneous injection |
| 100 mg inclisiran sodium | EXPERIMENTAL | Subcutaneous injection |
| Inclisiran-only | EXPERIMENTAL | Participants received subcutaneous injections of inclisiran 300 milligrams (mg) on Day 1 and every 180 days thereafter for up to 4 years. |
| Switching | ACTIVE_COMPARATOR | Participants received self-administered subcutaneous injections of evolocumab 140 mg on Day 1 and every 14 days thereafter until Day 336. Then, participants received subcutaneous injections of inclisiran 300 mg on Day 360 and every 180 days thereafter for up to 4 years. |
| ALN-PCSSC | EXPERIMENTAL | 300 milligrams (mg) administered subcutaneous (SC) on Day 1. Participants with a mean serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels not suppressed by \>70% at Day 60 or Day 90, as compared to baseline, will receive a second dose at Day 90 or Day 104, respectively, based on PCSK9 levels from the previous visit. Participants also received standard of care as background therapy. |
| ALN-PCSSC 200 mg (bi-annual dosing) | EXPERIMENTAL | ALN-PCSSC 200 milligram (mg) SC administration once at Day 1 |
| ALN-PCSSC 300 mg (bi-annual dosing) | EXPERIMENTAL | ALN-PCSSC 300 mg SC administration once at Day 1 |
| ALN-PCSSC 500 mg (bi-annual dosing) | EXPERIMENTAL | ALN-PCSSC 500 mg SC administration once at Day 1 |
| Normal Saline (bi-annual dosing) | PLACEBO_COMPARATOR | Saline SC administration once at Day 1 |
| ALN-PCSSC 100 mg (quarterly dosing) | EXPERIMENTAL | ALN-PCSSC 100 mg SC administration twice at Day 1 and Day 90 |
| ALN-PCSSC 200 mg (quarterly dosing) | EXPERIMENTAL | ALN-PCSSC 200 mg SC administration twice at Day 1 and Day 90 |
| ALN-PCSSC 300 mg (quarterly dosing) | EXPERIMENTAL | ALN-PCSSC 300 mg SC administration twice at Day 1 and Day 90 |
| Normal Saline (quarterly dosing) | PLACEBO_COMPARATOR | Saline SC administration twice at Day 1 and Day 90 |
| Arm A (inclisiran - currently marketed formulation) | ACTIVE_COMPARATOR | Inclisiran 284 mg × 1 single dose on Day 1 |
| Arm B (inclisiran - formulation containing PS80) | EXPERIMENTAL | Inclisiran 284 mg × 1 single dose on Day 1 |
| 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) | EXPERIMENTAL | 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) x 1 dose (n=15) at Day 1 |
| 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) | EXPERIMENTAL | 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) x 1 dose (n=15) at Day 1 |
| Inclisiran (normal renal function) | EXPERIMENTAL | Participants will receive a single dose of 300 milligram (mg) inclisiran administered by SC injection on Day 1. Normal renal function is defined as estimated creatinine clearance (CrCl) of ≥90 milliliter (mL)/minute (min). |
| Inclisiran (mild renal impairment) | EXPERIMENTAL | Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Mild renal impairment is defined as CrCl ranging from 60 to 89 mL/min. |
| Inclisiran (moderate renal impairment) | EXPERIMENTAL | Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Moderate renal impairment is defined as CrCl ranging from 30 to 59 mL/min. |
| Inclisiran (severe renal impairment) | EXPERIMENTAL | Participants will receive a single dose of 300 mg inclisiran administered by SC injection on Day 1. Severe renal impairment is defined as CrCl ranging from 15 to 29 mL/min. |
| Name | Type | Description |
|---|---|---|
| Placebo | DRUG | The participants will receive placebo subcutaneous at randomization (Day 1, Baseline visit) and Day 90 |
| Inclisiran | DRUG | The participants will receive Inclisiran sodium 300 mg subcutaneous at randomization (Day 1, Baseline visit) and Day 90 |
| Matching Placebo for Inclisiran | DRUG | Matching s.c. placebo |
| Ezetimibe | DRUG | 10 mg over-encapsulated tablet taken once a day from Day 1 through Day 149 |
| Matching Placebo for Ezetimibe | DRUG | 0mg over-encapsulated placebo tablet taken once a day from Day 1 through Day 149 |
| Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL | DRUG | Subcutaneous injection in pre-filled syringe. |
| Placebo in 1.5ml | DRUG | Matching placebo in 1.5ml solution for injection |
| Inclisiran sodium 300 mg | DRUG | Subcutaneously administered on Days 1, Month 3 (Day 90), and every 6 months thereafter. |
| Behavioural Support | BEHAVIORAL | Regular telephone based behavioural support programme delivered throughout the study period, as measured by point of care testing device. |
| Background lipid lowering therapy | DRUG | lipid-lowering therapy (such as a statin and/or ezetimibe) as background therapy |
| inclisiran sodium | DRUG | Subcutaneously injected on Day 1, 90 and 270 (Core Part). Subcutaneously injected on Day 360 and every 6 months thereafter until EOS visit (Extension Part) |
| Inclisiran Sodium for injection | DRUG | Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand. |
| Placebos | DRUG | Sterile normal saline (0.9% sodium chloride in water for injection) |
| Evolocumab | DRUG | Evolocumab is a fully human monoclonal antibody that inhibits PCSK9. |
| ALN-PCSSC | DRUG | ALN-PCSSC is a small interfering ribonucleic acid (siRNA) that inhibits PCSK9 synthesis and is given as SC injections. |
| Standard of Care | DRUG | Included maximally-tolerated statin therapy and/or other low density lipoprotein-cholesterol (LDL-C)-lowering therapies. |
| Normal Saline | DRUG | Saline (sterile, normal, 0.9%) solution given as SC injections |
| Inclisiran formulation containing PS80 | DRUG | Inclisiran 284 mg |
| Currently marketed inclisiran formulation | DRUG | Inclisiran 284 mg |
| 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) | DRUG | 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran) in 0.5 mL solution. Subcutaneous administration at Day 1 |
| 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) | DRUG | 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) in 1.5 mL solution. Subcutaneous administration at Day 1 |
Inclusion Criteria: Participant eligible for inclusion in this study must meet all the following criteria: At Screening: 1. Signed informed consent must be obtained prior to participation in the study. 2. Males and females, ≥18 years of age at the time of providing written informed consent. 3. Ab...
ALN-PCSSC is an investigational small molecule being developed for homozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease. It is being studied to evaluate its effect on lowering low density lipoprotein cholesterol (LDL-C) in these patient populations.
ALN-PCSSC is being developed by Novartis AG, which trades under the ticker symbol NVS. The company is conducting clinical trials to evaluate the drug's safety and efficacy in patients with cardiovascular conditions.
ALN-PCSSC is in Phase 2 clinical development. It is an investigational drug and has not been approved by regulatory authorities. Two Phase 2 trials have been completed to evaluate its effects on LDL-C levels in patients with familial hypercholesterolemia and atherosclerotic cardiovascular disease.
ALN-PCSSC has completed two Phase 2 clinical trials. NCT02597127 enrolled 501 participants with atherosclerotic cardiovascular disease, familial hypercholesterolemia, or diabetes. NCT02963311 enrolled 9 participants with homozygous familial hypercholesterolemia. Both trials were completed and evaluated the drug's effect on LDL-C.
ALN-PCSSC is a small molecule designed to lower low density lipoprotein cholesterol (LDL-C). It is being studied in patients with homozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease to assess its ability to reduce LDL-C levels.