Leqvio

Description for Leqvio

LEQVIO contains inclisiran sodium, a small interfering RNA (siRNA) directed to PCSK9 (proprotein convertase subtilisin kexin type 9) mRNA. Inclisiran contains a covalently linked ligand containing three Nacetylgalactosamine (GalNAc) residues to facilitate delivery to hepatocytes. With one exception, the 2'ribose moieties of the inclisiran sodium are present as 2'-F or 2'-OMe ribonucleotide. In addition, six of the terminal phosphodiester backbones are present as phosphorothioate linkages as indicated below.

The molecular formula of inclisiran sodium is C₅₂₉H₆₆₄F₁₂N₁₇₆Na₄₃O₃₁₆P₄₃S₆ and its molecular weight is 17,284.72 g/mol. It has the following structural formula:

Abbreviations: Af = adenine 2'-F ribonucleotide; Cf = cytosine 2'-F ribonucleotide; Gf = guanine 2'-F ribonucleotide; Am = adenine 2'-OMe ribonucleotide; Cm = cytosine 2'-OMe ribonucleotide; Gm = guanine 2'-OMe ribonucleotide; Um = uracil 2'-OMe ribonucleotide; L96 = triantennary GalNAc (N-acetyl-galactosamine)

LEQVIO is a sterile, preservative-free, clear, and colorless to pale yellow solution for subcutaneous use in a prefilled syringe. Each syringe contains 1.5 mL of solution containing the equivalent of 284 mg inclisiran (present as 300 mg inclisiran sodium salt). LEQVIO is formulated in Water for Injection and may also contain sodium hydroxide and/or phosphoric acid for pH adjustment to a target pH of 7.0.

ADVERSE REACTIONS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in Table 1 are derived from 3 placebo-controlled trials that included 1,833 patients treated with LEQVIO, including 1,682 exposed for 18 months (median treatment duration of 77 weeks) [see Clinical Studies (14)]. The mean age of the population was 64 years, 32% of the population were women, 92% were White, 6% were Black or African American, 1% were Asian, and < 1% were other races; 6% identified as Hispanic or Latino ethnicity. At baseline, 12% of patients had a diagnosis of HeFH and 85% had clinical atherosclerotic cardiovascular disease (ASCVD).

Adverse reactions reported in at least 3% of LEQVIO-treated patients, and more frequently than in placebotreated patients, are shown in Table 1.

Table 1: Adverse Reactions Occurring in Greater Than or Equal to 3% of LEQVIO-treated Patients and More Frequently than with Placebo (Studies 1, 2, and 3)

Adverse Reactions	Placebo (N = 1,822) %	LEQVIO (N = 1,833) %
Injection site reaction†	2	8
Arthralgia	4	5
Bronchitis	3	4
†includes related terms such as: injection site pain, erythema and rash

Adverse reactions led to discontinuation of treatment in 2.5% of patients treated with LEQVIO and 1.9% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with LEQVIO were injection site reactions (0.2% versus 0% for LEQVIO and placebo, respectively).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of LEQVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity: angioedema, rash, and urticaria.

Drug Interactions for Leqvio

No information provided

Warnings for Leqvio

Included as part of the PRECAUTIONS section.

Precautions for Leqvio

No information provided

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, Sprague-Dawley rats were administered subcutaneous doses of 40, 95, or 250 mg/kg inclisiran once every 28 days (1, 3, or 8 times the MRHD, based on BSA comparison/dose). Inclisiran was not carcinogenic up to the highest dose tested.

In a 26-week study in RasH2Tg mice, subcutaneous doses of 300, 600, or 1,500 mg/kg once every 28 days were administered. Inclisiran was not carcinogenic up to the highest dose tested.

Inclisiran was not mutagenic or clastogenic in a standard battery of genotoxicity tests, including a bacterial mutagenicity assay, an in vitro chromosome aberration assay using human peripheral lymphocytes, and an in vivo bone marrow micronucleus assay in rats.

Fertility and early embryonic-development studies were conducted in male and female rats. In male rats, inclisiran was administered subcutaneously at dose levels of 10, 50, and 250 mg/kg every 2 weeks for 4 weeks before cohabitation through mating, and until termination between Days 64 and 67. In female rats, inclisiran was administered subcutaneously at dose levels of 10, 50, and 250 mg/kg once every 4 days beginning 14 days prior to cohabitation and through mating, followed by 10, 50, or 150 mg/kg once daily during the gestation period up to Gestation Day 7. There were no adverse effects on fertility up to the highest dose examined, corresponding to 8 times the MRHD, based on BSA comparison/dose.

OVERDOSAGE

No information provided

Contraindications for Leqvio

LEQVIO is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO. Serious hypersensitivity reactions have included angioedema [see Adverse Reactions (6.2)].

Clinical Pharmacology for Leqvio

Mechanism of Action

Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

Pharmacodynamics

Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post dose. Mean reductions of 38% to 51% for LDL-C were observed 30 to 180 days post dose. At Day 180, LDL-C levels were still reduced by approximately 53%.

Following a dose at Day 1 and Day 90 of 284 mg of inclisiran, mean serum PCSK9 levels were reduced by approximately 75% and 69% at Day 120, and Day 180, respectively.

In the clinical studies, following four doses of LEQVIO at Day 1, Day 90 (3 months), Day 270 (~6 months) and Day 450 (~12 months), LDL-C, total cholesterol, ApoB, and non-HDL-C were reduced [see Clinical Studies (14)].

Cardiac Electrophysiology

At a dose 3 times the maximum recommended dose, inclisiran does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Absorption

Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose proportional manner over a range from 25 mg to 800 mg of inclisiran sodium. At the recommended dosing regimen of 284 mg of LEQVIO, plasma concentrations reached peak in approximately 4 hours post dose with a mean C_max of 509 ng/mL. Concentrations reached undetectable levels after 24 to 48 hours post dosing. The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7,980 ng*h/mL. Pharmacokinetic findings following multiple subcutaneous administrations of LEQVIO were similar to singledose administration.

Distribution

Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of LEQVIO to healthy adults, the apparent volume of distribution is approximately 500 L. Inclisiran has been shown to have high uptake into, and selectively for the liver, the target organ for cholesterol lowering.

Elimination

The terminal elimination half-life of LEQVIO is approximately 9 hours, and no accumulation occurs with multiple dosing. Approximately 16% of LEQVIO is cleared through the kidney.

Metabolism

Inclisiran is primarily metabolized by nucleases to shorter nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters.

Specific Populations

Male and Female Patients and Racial or Ethnic Groups

A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence inclisiran pharmacokinetics.

Patients with Renal Impairment

Pharmacokinetic analysis of data from a dedicated renal impairment study reported increases in inclisiran C_max and AUC of approximately 2.3 to 3.3-fold and 1.6 to 2.3-fold, respectively, in patients with mild, moderate or severe renal impairment, relative to patients with normal renal function. Despite the higher plasma exposures, reductions in LDL-C were similar across all groups based on renal function.

Patients with Hepatic Impairment

Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported increases in inclisiran C_max and AUC of approximately 1.1- to 2.1-fold and 1.3- to 2.0-fold, respectively, in patients with mild and moderate hepatic impairment, relative to patients with normal hepatic function. Despite the higher plasma inclisiran exposures, reductions in LDL-C were similar between the groups of patients administered inclisiran with normal hepatic function and mild hepatic impairment. In patients with moderate hepatic impairment, baseline PCSK9 levels were lower and reductions in LDL-C were less than those observed in patients with normal hepatic function. LEQVIO has not been studied in patients with severe hepatic impairment.

Drug Interaction Studies

No formal clinical drug interaction studies have been performed. The components of LEQVIO are not substrates, inhibitors or inducers of cytochrome P450 enzymes or transporters. In a population pharmacokinetic analysis, concomitant use of inclisiran did not have a clinically significant impact on atorvastatin or rosuvastatin concentrations. LEQVIO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes or transporters.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of inclisiran.

The immunogenicity of LEQVIO has been evaluated using screening and confirmatory immunoassays for the detection of binding anti-inclisiran antibodies.

Samples from 1,830 patients in the placebo-controlled clinical trials were tested for anti-drug antibodies [see Clinical Studies (14)]. Confirmed positivity was detected in 33 (2%) patients prior to receiving LEQVIO and in 90 (5%) patients during the 18 months of treatment with LEQVIO. Approximately 31 (2%) LEQVIO-treated patients with a negative sample at baseline had a persistent anti-inclisiran antibody response, defined as two confirmed positive samples separated by at least 16 weeks or a single confirmed positive final sample. There was no identified clinically significant effect of anti-inclisiran antibodies on pharmacodynamics, safety, or effectiveness of LEQVIO over the treatment duration of 18 months. However, the long-term consequences of continuing LEQVIO treatment in the presence of anti-inclisiran binding antibodies are unknown.

Patient Information for Leqvio

Pregnancy

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LEQVIO should be discontinued [see Use in Specific Populations (8.1)].

Injection Site Reactions

Advise patients that injection site reactions can occur with LEQVIO [see Adverse Reactions (6.1)].

The following information is intended for healthcare professionals only.

This Instructions for Use contains information on how to inject LEQVIO using the prefilled syringe.

Important Information You Need to Know Before Injecting LEQVIO:

• Do not use the prefilled syringe if any of the seals on the outer carton or the seal of the plastic tray are broken.
• Do not remove the needle cap until you are ready to inject.
• Do not use if the prefilled syringe has been dropped after removing the needle cap.
• Do not try to re-use or take apart the prefilled syringe.

Step 1. Inspect the prefilled syringe It should appear clear and colorless to pale yellow. Do not use if particulate matter or discoloration is seen. You may see air bubbles in the liquid, which is normal. Do not try to remove the air. Do not use the prefilled syringe if it looks damaged or if any of the solution for injection has leaked out of the prefilled Do not use the prefilled syringe after the expiration date (EXP), which is printed on the prefilled syringe label and
Step 2. Select and prepare the injection site Choose an injection site in the abdomen, upper arm, or thigh (see Figure A). Do not inject in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, or skin Wipe the skin with an alcohol swab. Let the injection site dry before you inject the dose.
Step 3. Remove needle cap Firmly pull straight to remove the needle cap from the prefilled syringe (see Figure B). You may see a drop of liquid at the end of the needle. This is normal. Do not put the needle cap back on. Throw it away. Note: Do not remove the needle cap until you are ready to inject. Early removal of the needle cap prior to injection can lead to drying of the drug product within the needle, which can resultin needle clogging.
Step 4. Insert the needle Gently pinch the skin at the injection site and hold the pinch throughout the injection. With the other hand insert the needle into the skin at an angle of approximately 45 degrees as shown (see Figure C).
Step 5. Inject Continue to pinch the skin. Slowly press the plunger as far as it will go (see Figure D). This will make sure that a full dose is injected. Note: If you cannot depress the plunger following insertion of the needle, use a new prefilled syringe.
Step 6. Complete injection and dispose of the prefilled syringe Remove the prefilled syringe from the injection site. Do not put the needle cap back on. Dispose of the prefilled syringe in a FDA-cleared sharps disposal container right away after use.

For more information, visit www.leqvio.com  or call 1-833-LEQVIO2 (1-833-537-8462).

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis

This Instructions for Use has been approved by the U.S. Food and Drug Administration.