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39494511000001103

New Medicines

LeqvioHypercholesterolaemia, elevated LDL-cholesterol (LDL-C) despite maximum tolerated doses of LDL-C lowering therapies.

Information

Leqvio
New molecular entity
Novartis
Novartis

Development and Regulatory status

Launched
Launched
Launched
June 2021
Jan 22Available in the US from specialty distributors. Is also available in the Netherlands [29,30].
Dec 21Approved in the US for use as an adjunct to maximum-dose statin drugs for people who need further LDL-cholesterol reduction to reach targets. Novartis plan to launch in January [28].
Oct 21NHS England publishes a Medicines Optimisation pack for inclisiran, in which it explains that the NHS will fund inclisiran centrally from a national NHS budget in order that local finances are not a barrier to the local uptake of inclisiran. Inclisiran will be available in primary care as a personally administered item via an FP34D form or on an FP10 prescription, and will be listed in the Drug Tariff (DT) at a reimbursed price of £55 per injection. The cost to the CCG/primary care prescribing budget will be the DT price. A separate payment will be made to Novartis from a central NHS budget for the difference between the commercial agreement price and the DT price. Hospitals ordering stock of inclisiran will be charged the confidential commercial agreement price [27].
Sep 21Novartis announces commercial agreement with the NHS in England to provide inclisaran with discount (undisclosed) making it available for administration in primary care. The agreement follows positive NICE draft guidance and commits to deliver inclisiran access via a population health management approach identifying eligible patients across England, allowing ~300,000 people to receive it over the next three years [25,26].
Jul 21Re-filed in the US with a new manufacturing location in Austria [23], , with a PDUFA date of 1st January 2022 [24].
Jun 21Launched in the UK. Adjunct to diet in primary hypercholesterolaemia or mixed dyslipidaemia: with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with maximal tolerated dose of a statin; or alone or with other lipid-lowering therapies when a statin is contraindicated or not tolerated. Price for 284mg/1.5ml soln for inj in pre-filled syringe, 1=£1987.36 (hospital only)[22].
Jan 21Novartis received a complete response letter (CRL) from the FDA due to unresolved facility inspection-related conditions at a third-party manufacturing facility in Europe. The FDA has not raised any concerns related to the efficacy or safety of inclisiran. Response to CRL planned to be submitted Q2 - Q3 2021 [21].
Dec 20Approved in EU [20]
Oct 20Recommended for EU approval by CHMP - the full indication is "in adults with primary hypercholesterolaemia (heterozygous familial and non‑familial) or mixed dyslipidaemia, as an adjunct to diet: in combination with a statin or statin with other lipid‑lowering therapies in patients unable to reach LDL‑C goals with the maximum tolerated dose of a statin, or; alone or in combination with other lipid‑lowering therapies in patients who are statin‑intolerant, or for whom a statin is contraindicated" [19].
Feb 20Filed in EU via centralised procedure [15].
Feb 20Analysts predict this will be one of the top 10 most-anticipated new US drug launches of 2020 based on estimated global sales in 2024 [14].
Jan 20Novartis announces plans to partner with the NHS in a world-first approach to addressing CV disease. Inclisiran will be studied in UK patients as part of a large-scale NHS clinical trial, which is expected to start later this year. If successful, the cholesterol lowering treatment is expected to be made available through a “population-level agreement” [13].
Dec 19Filed in US [16].
Nov 19Novartis is to acquire The Medicines Company, adding inclisiran, a potentially transformational investigational cholesterol-lowering therapy to its portfolio [12].
Sep 19Regulatory filings in US planned for 4th quarter of this year and in EU for first quarter of 2020 [10].
Aug 19Regulatory submissions to the US FDA and EMA and expected in Q4 2019 and Q1 2020 respectively.[9]
Mar 19The Medicines Company announced plans to file for FDA approval during 2019 and a European filing is planned for Q1 2020.[8]
Feb 18Will be filed in EU using centralised procedure [6].
Nov 17The phase III program for inclisiran comprises four trials ORION-5, ORION-9, ORION-10 and ORION-11 which will support filings in the US and EU at or around the end of 2019 [5]
Apr 17The Medicines Company and RNA biotech partner Alnylam have set out a new PIII trial for inclisiran, which it hopes will get over the line for approval. After its end-of-phase-2 meeting with the FDA, the pair are planning a 3,000-patient-strong test focusing in on atherosclerotic cardiovascular disease and familial hypercholesterolemia. The primary endpoint for these pivotal trials will be LDL-C change from baseline. Although not required by the FDA, Med Co would also undertake a large cardiovascular outcomes trial in as many as 14,000 patients with ASCVD and/or risk equivalents, such as diabetes. The design of this trial has already been approved by the FDA, with the primary efficacy endpoint being a composite of coronary heart disease death, nonfatal myocardial infarction (heart attack) and fatal and nonfatal ischemic stroke. The trial could be a long one, and long enough to build up data on the number of events to provide overwhelming statistical power to ascertain treatment group differences and maximize the clinical effect size associated with LDL-C lowering [3].

Category

PCSK9 synthesis inhibitor
The UK population has one of the highest average serum cholesterol levels, two thirds of the UK population have a serum cholesterol level greater than 5.2 mmol/L. High levels of cholesterol are associated with an increased mortality from cardiovascular disease
Hypercholesterolaemia, elevated LDL-cholesterol (LDL-C) despite maximum tolerated doses of LDL-C lowering therapies.
Subcutaneous injection

Further information

Yes

Trial or other data

Mar 22Inclisiran will be added to the PbR excluded drug list from April 2022 and will be reimbursed centrally by NHS England. NHS England shadowed this arrangement from 1 January 2022. Prior to this change (September – December 2021) trusts were charged the confidential contract price via the CAP portal when ordering stock of inclisiran and did not receive reimbursement [30].
Nov 20If approved, inclisiran would compete with evolocumab and alirocumab, which are both antibodies against PCSK9 given once or twice a month. Inclisiran is given twice a year and lowers cholesterol by interfering with the production of PCSK9 itself [8].
Mar 20March 20: current evidence on inclisiran published in two papers published in The NEJM (PIII trials in pts with atherosclerosis and in heterozygous familial hypercholesterolemia). [17,18]
Nov 19In the ORION-10 study of pts with ACSVD and elevated LDL, twice yearly injections with inclisiran reduced LDL-C levels by -58% with inclusiran vs. placebo (p<0.00001) at day 510. Inclusiran was well tolerated.[11]
Sep 19Inclisiran achieved primary and secondary endpoints in the PIII ORION-10 and ORION-9 trials, with no treatment-related liver or renal abnormalities observed in lab tests [10].
Aug 19Inclisiran acheived primary and secondary endpoints in the PIII ORION-11 trial (n=1617, ex-US). ORION-11 is a placebo-controlled, double-blind, randomised study evaluating the efficacy, safety, and tolerability of inclisiran 300 mg (s.c) at 0, 3 and thereafter 6 monthly in pts with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents and elevated LDL-C despite maximum tolerated dose of statin (+/-ezetimibe). The primary endpoints are percentage change in LDL-C from baseline to 17m and time-adjusted percentage change in LDL-C from baseline after 3m and up to 18m. Detailed results are expected in September 2019.[9]
May 19Further data from pivotal PIII trials are expected in Q3 2019.[8]
May 19Long-term data from the interim analysis of an extension of the ORION-1 PIII trial (n=290) showed that inclisiran consistently lowered LDL cholesterol by >50%. ORION-1, tested inclisiran in pts with atherosclerotic CVD and high LDL cholesterol levels despite taking the highest statin dose tolerable. Of the ORION-1 pts followed up over 1 year, 382 pts enrolled in the extension, with 290 receiving a 300-mg injection of inclisiran twice a year and 92 receiving evolocumab injections every two weeks for a year, before switching to inclisiran for 3 years. Inclisiran lowered LDL cholesterol levels by 51% through day 210, meeting its primary endpoint. Data for the second group are expected in 2022.[8]
Jun 18New data New data from ORION-1 PII trial presented at conference. SC injection of 300mg of inclisiran, at day-1 and day-90 lowered LDL-cholesterol at day-180 by >50% in patients with ASCVD and those considered ASCVD-risk equivalents, regardless of diabetes status [7].
Mar 17PII placebo controlled trial (ORION-1) in 497 patients found that a 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. The mean baseline LDL-C was approximately 130 mg/dL [1].

Evidence based evaluations

LeqvioHyperlipidaemia in adolescents (aged 12-17 years) with HeFH and HoFH

Information

Leqvio
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

A small interfering ribonucleic acid (RNAi) that inhibits PCSK9 synthesis
The UK population has one of the highest average serum cholesterol levels in the world. Two thirds have a serum cholesterol level greater than 5.2 mmol/L. Heterozygous familial hypercholesterolaemia is one of the most common familial conditions, with a prevalence of ~1 in 500. Homozygous familial hypercholesterolaemia is rare [1]. Children/young people with FH are most likely to be identified through cascade testing in a family where a mutation has been identified in an index case [2].
Hyperlipidaemia in adolescents (aged 12-17 years) with HeFH and HoFH
Subcutaneous injection

LeqvioCardiovascular risk reduction in people with pre-existing atherosclerotic CV disease

Information

Leqvio
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Phase III Clinical Trials
None
Phase III Clinical Trials

Category

A small interfering ribonucleic acid (RNAi) that inhibits PCSK9 synthesis [1].
Raised cholesterol increases the risks of heart disease and stroke. Globally, a third of ischaemic heart disease is attributable to high cholesterol. A 10% reduction in serum cholesterol in men aged 40 has been reported to result in a 50% reduction in heart disease within 5 years; the same serum cholesterol reduction for men aged 70 years can result in an average 20% reduction in heart disease occurrence in the next 5 years [4].
Cardiovascular risk reduction in people with pre-existing atherosclerotic CV disease
Subcutaneous injection