Prevymis Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics ................................................................................................................ 4

1.2 Geriatrics ................................................................................................................ 4

2 CONTRAINDICATIONS ................................................................................................. 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations ............................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.3 Reconstitution ........................................................................................................ 6

4.4 Administration ........................................................................................................ 8

4.5 Missed Dose ........................................................................................................... 9

5 OVERDOSAGE .............................................................................................................. 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 9

7 WARNINGS AND PRECAUTIONS ................................................................................ 10

7.1 Special Populations............................................................................................... 12

7.1.1 Pregnant Women ........................................................................................... 12

7.1.2 Breast-feeding ................................................................................................ 12

7.1.3 Pediatrics ........................................................................................................ 12

7.1.4 Geriatrics ........................................................................................................ 12

8 ADVERSE REACTIONS ................................................................................................ 12

8.1 Adverse Reaction Overview .................................................................................. 12

8.2 Clinical Trial Adverse Reactions ............................................................................ 13

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 15

8.5 Post-Market Adverse Reactions ........................................................................... 16

9 DRUG INTERACTIONS ................................................................................................ 16

9.1 Serious Drug Interactions ..................................................................................... 16

9.2 Drug Interactions Overview .................................................................................. 16

9.4 Drug-Drug Interactions ......................................................................................... 17

9.5 Drug-Food Interactions ......................................................................................... 27

9.6 Drug-Herb Interactions ......................................................................................... 27

9.7 Drug-Laboratory Test Interactions ........................................................................ 27

10 CLINICAL PHARMACOLOGY ....................................................................................... 27

10.1 Mechanism of Action ...................................................................................... 27

10.2 Pharmacodynamics ........................................................................................ 27

10.3 Pharmacokinetics ........................................................................................... 27

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 31

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 31

PART II: SCIENTIFIC INFORMATION ....................................................................................... 32

13 PHARMACEUTICAL INFORMATION ............................................................................ 32

14 CLINICAL TRIALS ........................................................................................................ 32

14.1 Clinical Trials by Indication ............................................................................. 32

Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant (HSCT): .......................................................................................................... 32

Adult CMV-seronegative Recipients of a Kidney Transplant from a CMV-seropositive Donor [D+/R-] ................................................................................................................. 38

15 MICROBIOLOGY ........................................................................................................ 42

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 43

PATIENT MEDICATION INFORMATION .................................................................................. 45

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

PREVYMIS® (letermovir) is indicated for:

• the prophylaxis of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).
• the prophylaxis of CMV disease in adult kidney transplant recipients who are at high risk (donor CMV-seropositive [D+]/recipient CMV-seronegative [R-]).

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Safety and efficacy were similar across older and younger subjects in the Phase 3 trials in HSCT recipients and in the Phase 3 trial in kidney transplant recipients.

2 CONTRAINDICATIONS

PREVYMIS® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Pimozide

Concomitant administration of PREVYMIS® may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, leading to QT prolongation and torsades de pointes (see 7 WARNINGS AND PRECAUTIONS and 9.2 Drug Interactions Overview).

Ergot Alkaloids

Concomitant administration of PREVYMIS® may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism (see 7 WARNINGS AND PRECAUTIONS and 9.2 Drug Interactions Overview).

Cyclosporine with lovastatin, rosuvastatin or simvastatin

Concomitant administration of PREVYMIS® when used in combination with cyclosporine is contraindicated as it may result in significantly increased lovastatin, rosuvastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis (see 7 WARNINGS AND PRECAUTIONS and 9.2 Drug Interactions Overview).

Cyclosporine with bosentan

Concomitant administration of PREVYMIS® when used in combination with cyclosporine is contraindicated as it may result in significantly increased concentrations of bosentan (see 7 WARNINGS AND PRECAUTIONS and 9.2 Drug Interactions Overview).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

PREVYMIS® Tablets

• Administer with or without food.
• Swallow tablets whole. Do not divide, crush or chew.

PREVYMIS® Injection

• PREVYMIS® injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.
• Do not administer as an IV bolus injection.
• Administer by intravenous (IV) infusion upon dilution via a peripheral catheter or central venous line over approximately 60 minutes.

PREVYMIS® tablet and injection may be used interchangeably at the discretion of the physician, and no dose adjustment is necessary.

4.2 Recommended Dose and Dosage Adjustment

Recommended Dosage

Adults:

The recommended dosage of PREVYMIS® is 480 mg administered once daily.

If PREVYMIS® is co-administered with cyclosporine, the dosage of PREVYMIS® should be decreased to 240 mg once daily (see Dosage Adjustment in Adults section below).

HSCT

PREVYMIS® should be started after HSCT. PREVYMIS® may be started on the day of transplant and no later than 28 days post-HSCT. PREVYMIS® may be started before or after engraftment. Continue PREVYMIS® through 100 days post-HSCT. In patients at risk for late CMV infection and disease, PREVYMIS® may be continued through 200 days post-HSCT.

Following completion of PREVYMIS® prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended.

Kidney Transplant

PREVYMIS® should be started on the day of transplant and no later than 7 days post-kidney transplant and continued through 200 days post-transplant.

Pediatrics (< 18 years of age):

Safety and efficacy of PREVYMIS® have not been established in pediatric patients less than 18 years of age.

Geriatrics (≥ 65 years of age):

No dose adjustment of PREVYMIS® is required based on age (see 10.3 Pharmacokinetics).

Dosage Adjustment in Adults

If PREVYMIS® is co-administered with cyclosporine, the dosage of PREVYMIS® should be decreased to 240 mg once daily (see 4.3 Reconstitution, 9 DRUG INTERACTIONS and 10.3 Pharmacokinetics).

• If cyclosporine is initiated after starting PREVYMIS®, the next dose of PREVYMIS® should be decreased to 240 mg once daily.
• If cyclosporine is discontinued after starting PREVYMIS®, the next dose of PREVYMIS® should be increased to 480 mg once daily.
• If cyclosporine dosing is temporarily interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS® is needed.

Renal Impairment

No dose adjustment of PREVYMIS® is required based on renal impairment (see Renal, Combined Renal and Hepatic Insufficiency and 10.3 Pharmacokinetics). There are no data in patients with end-stage renal disease (CrCl less than 10 mL/min), including patients on dialysis.

Hepatic Impairment

No dose adjustment of PREVYMIS® is required based on mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS® is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment (see Hepatic/Biliary/Pancreatic, Combined Renal and Hepatic Insufficiency and 10.3 Pharmacokinetics).

Combined Renal and Hepatic Impairment

PREVYMIS® is not recommended in patients with moderate hepatic impairment combined with moderate or severe renal impairment (CrCl less than 50 mL/min) (see Combined Renal and Hepatic Insufficiency and 10.3 Pharmacokinetics).

4.3 Reconstitution

Parenteral Products:

• Add one single-dose vial of PREVYMIS® injection to a 250 mL pre-filled IV bag containing either 0.9% sodium chloride injection or 5% dextrose injection and mix bag gently. Do not shake.
• Once diluted, the solution of PREVYMIS® is clear, and ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product. The diluted solution should be inspected visually for particulate matter and discoloration prior to administration.
• Discard if the diluted solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.

Storage of Diluted Solution

• The diluted solution can be stored for up to 24 hours at room temperature or up to 48 hours under refrigeration at 2°C to 8°C.
• This time includes storage of the diluted solution in the IV bag through the duration of infusion.

Compatible Diluents, Drug Products, and Other Materials Used for Intravenous Administration

Compatible Diluents

PREVYMIS® injection is compatible with 0.9% sodium chloride injection and 5% dextrose injection.

Compatible Drug Products

A study was conducted to evaluate physical compatibility of PREVYMIS® injection with injectable drug products. Compatibility was determined through visual observations, turbidity, and measurement of particulate matter. Compatible drug products are listed below.

PREVYMIS® should not be co-administered through the same IV line (or cannula) with other drug products and diluent combinations except those listed below.

The following compatible drug products^† may be co-administered with PREVYMIS® for injection when both drug products are in 0.9% Sodium Chloride via Y tubing only, as per the approved instructions of the respective drug products.

• Ampicillin sodium
• Anti-thymocyte globulin
• Caspofungin
• Daptomycin
• Fentanyl citrate
• Fluconazole
• Furosemide
• Human insulin
• Magnesium sulfate
• Methotrexate
• Micafungin

^† These injectable drug products are available in Canada

The following compatible drug products^† may be co-administered with PREVYMIS® for injection when both drug products are in 5% Dextrose via Y tubing only, as per the approved instructions of the respective drug products.

• Amphotericin B (lipid complex)^#
• Anidulafungin
• Cefazolin sodium
• Ceftriaxone sodium
• Famotidine
• Folic acid
• Ganciclovir sodium
• Hydrocortisone sodium succinate
• Morphine sulfate
• Norepinephrine bitartrate
• Pantoprazole sodium
• Potassium chloride
• Potassium phosphate
• Tacrolimus
• Telavancin
• Tigecycline

^† These injectable drug products are available in Canada

^# Amphotericin B (lipid complex) is compatible with PREVYMIS®. However, Amphotericin B (liposomal) is incompatible (see below Incompatible Drug Products and Other Materials Used for Intravenous Administration).

Compatible IV Bags and Infusion Set Materials

PREVYMIS® is compatible with the following IV bags and infusion set materials. Any IV bags or infusion set materials not listed below should not be used.

IV Bags Materials:

Polyvinyl chloride (PVC), ethylene vinyl acetate (EVA) and polyolefin (polypropylene and polyethylene)

Infusion Sets Materials:

PVC, polyethylene (PE), polybutadiene (PBD), silicone rubber (SR), styrene–butadiene copolymer (SBC), styrene-butadiene-styrene copolymer (SBS), polystyrene (PS)

Plasticizers:

Tris (2-ethylhexyl) trimellitate (TOTM), butyl benzyl phthalate (BBP)

Catheters:

Radiopaque polyurethane

Incompatible Drug Products and Other Materials Used for Intravenous Administration

Incompatible Drug Products

PREVYMIS® injection is physically incompatible with amiodarone HCl, amphotericin B (liposomal), aztreonam, cefepime HCl, ciprofloxacin, cyclosporine, diltiazem HCl, filgrastim, gentamicin sulfate, levofloxacin, linezolid, lorazepam, midazolam HCl, mycophenolate mofetil HCl, ondansetron, and palonosetron.

Incompatible IV Bags and Infusion Set Materials

PREVYMIS® injection is incompatible with diethylhexyl phthalate (DEHP) plasticizers and polyurethane-containing IV administration set tubing.

4.4 Administration

PREVYMIS® injection is supplied in 30 mL single-dose vials containing either 240 mg (12 mL per vial) or 480 mg (24 mL per vial). The preparation and administration instructions are the same for either dose.

PREVYMIS® vials are for single use only. Discard any unused portion.

• The diluted solution must be administered through a sterile 0.2 micron or 0.22 micron PES in-line filter.
• Do not administer the diluted solution through a filter other than a sterile 0.2 micron or 0.22 micron PES in-line filter.
• Administer as an IV infusion upon dilution only. Do not administer as an IV push or bolus.
• After dilution, administer PREVYMIS® via IV infusion via peripheral or central venous catheter using a total time of approximately 60 minutes. Administer the entire contents of the IV bag.

Preparation

• PREVYMIS® must be diluted prior to IV use.
• Inspect vial contents for discoloration and particulate matter prior to dilution. PREVYMIS® injection is a clear colorless solution and may contain a few product-related small translucent or white particles.
• Do not use the vial if the solution is cloudy, discolored, or contains matter other than a few small translucent or white particles.
• Do not use PREVYMIS® injection with IV bags and infusion set materials containing polyurethane or the plasticizer diethylhexyl phthalate (DEHP). Materials that are phthalate-free are also DEHP-free.
• Do not shake PREVYMIS® vial.

4.5 Missed Dose

Instruct patients that if they miss a dose of PREVYMIS®, they should take it as soon as they remember. If they do not remember until it is time for the next dose, instruct them to skip the missed dose and go back to the regular schedule. Instruct patients not to double their next dose or take more than the prescribed dose.

5 OVERDOSAGE

During Phase 1 clinical trials, 86 healthy subjects received doses ranging from 720 mg/day to 1440 mg/day of PREVYMIS® for up to 14 days. The adverse reaction profile was similar to that of the clinical dose of 480 mg/day. There is no specific antidote for overdose with PREVYMIS®. In case of overdose, it is recommended that the patient be monitored for adverse reactions and appropriate symptomatic treatment instituted.

It is unknown whether dialysis will result in meaningful removal of PREVYMIS® from systemic circulation.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Tablet:

PREVYMIS® 240 mg tablet is a yellow oval tablet. Each tablet is debossed with “591” on one side and Corporate logo on the other side. The 240 mg tablets are packaged in aluminum foil blister and lidding in cartons of 28 tablets.

PREVYMIS® 480 mg tablet is a pink oval, bi-convex tablet. Each tablet is debossed with “595” on one side and Corporate logo on the other side. The 480 mg tablets are packaged in aluminum foil blister and lidding in cartons of 28 tablets.

Solution for Injection:

PREVYMIS® for injection 240 mg/12 mL (20 mg/mL) is supplied in a single-dose vial.

PREVYMIS® for injection 480 mg/24 mL (20 mg/mL) is supplied in a single-dose vial.

7 WARNINGS AND PRECAUTIONS

General

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

• The concomitant use of PREVYMIS® and certain drugs may result in known or potentially significant drug interactions, some of which may lead to:

  • Possible clinically significant adverse reactions from greater exposure of concomitant drugs or PREVYMIS®.
  • Significant decrease of concomitant drug plasma concentrations which may lead to reduced therapeutic effect of the concomitant drug.

See Table 5 for steps to prevent or manage these known or potentially significant drug interactions, including dosing recommendations (see 2 CONTRAINDICATIONS, 9.2 Drug Interactions Overview and 9.4 Drug-Drug Interactions). Consider the potential for drug interactions prior to and during PREVYMIS® therapy; review concomitant medications during PREVYMIS® therapy; and monitor for the adverse reactions associated with the concomitant drugs.

PREVYMIS® should be used with caution with drugs that are CYP3A substrates with narrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine¹) as co-administration may result in increases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustment of co-administered CYP3A substrates is recommended (see Table 5, 9.2 Drug Interactions Overview and 9.4 Drug-Drug Interactions).

¹ Not marketed in Canada.

Co-administration of PREVYMIS® with strong and moderate inducers of transporters (e.g., P-gp) and/or enzymes (e.g. UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations.

Rifampin co-administration resulted in an initial increase in letermovir plasma concentrations

(due to OATP1B1/3 inhibition) that is not clinically significant, followed by clinically relevant decreases in letermovir plasma concentrations with continued rifampin co-administration. This may result in loss of prophylactic efficacy and necessitate initiation of anti-CMV therapy for CMV reactivation and/or disease.

Co-administration of PREVYMIS® may result in increases in the plasma concentrations of cyclosporine, tacrolimus, and sirolimus. Close monitoring and/or dose adjustment of cyclosporine, tacrolimus, and sirolimus is recommended when co-administered with PREVYMIS®.

Hepatic/Biliary/Pancreatic

Hepatic Insufficiency

Exposure to PREVYMIS® is increased 1.6- to 3.8-fold in subjects with moderate and severe hepatic impairment. No dose adjustment of PREVYMIS® is required based on mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS® is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment (see 4.2 Recommended Dose and Dosage Adjustment, Combined Renal and Hepatic Insufficiency and 10.3 Pharmacokinetics).

Renal

Renal Insufficiency

Exposure to PREVYMIS® is increased 1.4- to 1.9-fold in subjects with moderate and severe renal impairment. No dose adjustment of PREVYMIS® is required based on renal impairment (see 4.2 Recommended Dose and Dosage Adjustment, Combined Renal and Hepatic Insufficiency and 10.3 Pharmacokinetics). There are no data in patients with end-stage renal disease (CrCl less than 10 mL/min), including patients on dialysis.

In patients with moderate or severe renal impairment (CrCl less than 50 mL/min) receiving

PREVYMIS® injection, accumulation of the IV vehicle, hydroxypropyl betadex, could occur. Serum creatinine levels should be closely monitored in these patients.

Combined Renal and Hepatic Insufficiency

PREVYMIS® is not recommended in patients with moderate hepatic impairment combined with moderate or severe renal impairment (see 4.2 Recommended Dose and Dosage Adjustment and 10.3 Pharmacokinetics).

Reproductive Health: Female and Male Potential

• Fertility

There were no effects on female fertility in rats. Impairment of fertility was observed in male rats, but not in male mice or male monkeys (see 16 NON-CLINICAL TOXICOLOGY). Testicular toxicity in rats appears to be species-specific, and the relevance to humans is unknown. In the Phase 3 trials in HSCT and kidney transplant recipients, there was no evidence of letermovir-related testicular toxicity (see 8.2 Clinical Trials Adverse Reactions, 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

7.1 Special Populations

7.1.1 Pregnant Women

No human data are available to establish whether or not PREVYMIS® poses a risk to pregnancy outcomes, therefore, the potential risk to humans is unknown. PREVYMIS® should not be used in pregnancy unless benefit outweighs the risk.

Embryofetal toxicity was observed in rats and rabbits at maternally toxic systemic AUC exposures of approximately 11- and 2-fold, respectively, the AUC at the recommended human dose (RHD). In the rat pre-and postnatal development study, no developmental toxicity was observed up to the highest maternal systemic AUC exposure (approximately 2-fold the AUC at the RHD).

In pregnant rats, letermovir was able to cross the placenta (see 10.3 Pharmacokinetics).

7.1.2 Breast-feeding

It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.

When administered to lactating rats, letermovir was present in milk, without effects on growth and development in nursing pups.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PREVYMIS® and any potential adverse effects on the breastfed child from PREVYMIS® or from the underlying maternal condition.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): Safety and efficacy were similar across older and younger subjects in the Phase 3 trials in HSCT recipients and in the Phase 3 trial in kidney transplant recipients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety summary for PREVYMIS® in HSCT recipients was based on data from a randomized, placebo-controlled Phase 3 clinical trials (P001 and P040) in which CMV seropositive HSCT recipients received letermovir or placebo. The safety summary for PREVYMIS® in kidney transplant recipients was based on data from a randomized, active comparator-controlled Phase 3 clinical trial P002 in which kidney transplant recipients [D+/R-] received letermovir or valganciclovir.

In P001, the most commonly reported adverse reactions in subjects treated with PREVYMIS® through Week 14 post-HSCT and followed for safety through Week 24 post-HSCT were nausea, diarrhea, and vomiting. In P002, the most commonly reported adverse reactions in subjects treated with PREVYMIS® or valganciclovir through Week 28 post-kidney transplant were leukopenia, neutropenia, and white blood cell count decreased. In P040, the most commonly reported adverse reactions in subjects treated with PREVYMIS® from Week 14 post-HSCT through Week 28 post-HSCT were nausea and vomiting.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT

Prophylaxis Through Week 14 (~100 days) Post-HSCT

The safety of PREVYMIS® was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P001) through Week 14 post-HSCT and were followed for safety through Week 24 post-HSCT (see 14 CLINICAL TRIALS).

The most commonly reported adverse reactions occurring in at least 1% of subjects in the PREVYMIS® group through Week 24 post-HSCT and at a frequency greater than placebo were: nausea, diarrhea, and vomiting (see Table 2).

Table 2 - P001 Adverse Reactions Reported in ≥1% HSCT Recipients in the PREVYMIS® Group and at a Frequency Greater than Placebo Through Week 24 Post-Transplant

Serious adverse reactions through week 24 post-HSCT were reported in 6 (1.1%) subjects with 3 (0.8%) in the PREVYMIS® group and 3 (1.6%) in the placebo group. The reported serious adverse reactions, which had a temporal association but no other plausible causal relationship to study treatment, were pancytopenia, thrombocytopenia, and delayed engraftment in the letermovir group and Bowen’s disease, mental status changes, and acute kidney injury in the placebo group.

Cardiac Adverse Events:

Cardiac adverse events were more common in subjects receiving PREVYMIS® (13%) compared to subjects receiving placebo (6%). The most common cardiac adverse events were tachycardia (reported in 4% of PREVYMIS® subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3.5% of PREVYMIS® subjects and in 1% of placebo subjects). These adverse events were mostly considered mild or moderate in severity.

Hypersensitivity was reported with PREVYMIS® in one subject.

Overall, similar proportions of subjects in each group discontinued study medication due to an adverse reaction (4.8% PREVYMIS® vs. 3.6% placebo). The most frequently reported adverse reactions that led to discontinuation of PREVYMIS® were nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%).

Prophylaxis From Week 14 (~100 days) Through Week 28 (~200 days) Post-HSCT

The safety of PREVYMIS® was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P040) in which 218 subjects who completed PREVYMIS® prophylaxis through ~100 days post-HSCT were randomized to treatment with PREVYMIS® (N=144) or placebo (N=74) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT.

The adverse reactions observed were consistent with those observed in P001. The most commonly reported adverse reactions occurring in at least 1% of subjects in the PREVYMIS® group and at a frequency greater than placebo were: nausea (2.1%) and vomiting (1.4%). A total of 5% of subjects in the PREVYMIS® group and 1% of subjects in the placebo group discontinued due to adverse events; none of the adverse events were considered to be related to study medication (PREVYMIS® or placebo).

The cardiac adverse event rate (regardless of investigator-assessed causality) was 4% in the PREVYMIS® and placebo groups; no cardiac adverse event was reported more than once in either group.

Adult Kidney Transplant Recipients [D+/R-]

The safety of PREVYMIS® was evaluated in a Phase 3 randomized, double-blind, active comparator-controlled trial (P002) in which 589 subjects were treated with PREVYMIS® (N=292) or valganciclovir (N=297) through Week 28 post-transplant.

The most commonly reported adverse reactions occurring in at least 2% of subjects in the PREVYMIS® group or valganciclovir group are shown in Table 3.

Table 3- P002 Adverse Reactions Reported in ≥2% Kidney Transplant Recipients in the PREVYMIS® Group or Valganciclovir Group Through Week 28 Post-Transplant

Study medication was discontinued due to an adverse reaction in 2.7% of subjects in the PREVYMIS® group and 8.8% of subjects in the valganciclovir group. The most frequently reported adverse reactions that led to study medication discontinuation were neutropenia (PREVYMIS®, 1.4%; valganciclovir, 1.3%) and leukopenia (PREVYMIS®, 1.0%; valganciclovir, 5.4%).

The proportion of subjects with leukopenia or neutropenia (adverse events of leukopenia or neutropenia, total white blood cell count <3500 cells/μL, or absolute neutrophil count <1000 cells/μL) through Week 28 post-transplant was lower in the PREVYMIS® group compared with the valganciclovir group (PREVYMIS®, 26%; valganciclovir, 64%).

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT

Overall, the percentage of subjects with potentially clinically significant changes in laboratory values (e.g., hematology, chemistry, renal, and hepatic function) was similar in the PREVYMIS® and placebo groups. In P001, there were no differences in the incidence of or time to engraftment (defined as absolute neutrophil count ≥ 500/mm³ on 3 consecutive days after transplantation) between the PREVYMIS® and placebo groups. In Study P040 serum creatinine abnormalities > 1.5 mg/dL occurred in 15% of PREVYMIS and 8% of placebo subjects.

Biomarkers of testicular toxicity were evaluated in male subjects in P001 (see 16 NON-CLINICAL TOXICOLOGY). The changes from baseline in male sex hormones (serum inhibin B, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone) were similar in the PREVYMIS® and placebo groups.

Adult Kidney Transplant Recipients [D+/R-]

Selected laboratory abnormalities reported through Week 28 post-transplant are presented in the table below.

Table 4 - P002 Selected Laboratory Abnormalities

8.5 Post-Market Adverse Reactions

Not Applicable.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

Effect of Other Drugs on PREVYMIS®

Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) and P-glycoprotein (P-gp) transporters and UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) enzymes. Co-administration of PREVYMIS® with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations. If PREVYMIS® is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of PREVYMIS® is 240 mg once daily (see 4.2 Recommended Dose and Dosage Adjustment, 10.3 Pharmacokinetics, and Table 5).

Co-administration of PREVYMIS® with strong and moderate inducers of transporters (e.g., P-gp) and/or enzymes (e.g., UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations (see 7 WARNINGS AND PRECAUTIONS).

Rifampin co-administration resulted in an initial increase in letermovir plasma concentrations (due to OATP1B1/3 inhibition) that is not clinically significant, followed by clinically relevant decreases in letermovir plasma concentrations with continued rifampin co-administration. This may result in loss of prophylactic efficacy and necessitate initiation of anti-CMV therapy for CMV reactivation and/or disease (see 7 WARNINGS AND PRECAUTIONS).

Effect of PREVYMIS® on Other Drugs

Letermovir is a moderate inhibitor of CYP3A, based on clinical studies using midazolam as probe. Co-administration of PREVYMIS® with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates. PREVYMIS® is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions. PREVYMIS® should be used with caution with other CYP3A substrates and adverse reactions to these drugs monitored as appropriate (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS, and Table 5)

Letermovir is an inhibitor of OATP1B1/3 transporters BCRP, BSEP, MRP2, and UGT1A1. Co-administration of PREVYMIS® with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates (see Table 5).

The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS® is co-administered with cyclosporine. See the product monograph for cyclosporine for information on drug interactions with cyclosporine.

9.4 Drug-Drug Interactions

Established and Other Potentially Significant Drug Interactions

If dose adjustments of concomitant medications are made due to treatment with PREVYMIS®, doses should be readjusted after treatment with PREVYMIS® is completed.

Table 5 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with PREVYMIS® or are predicted drug interactions that may occur with PREVYMIS® (see 7 WARNINGS AND PRECAUTIONS and 10.3 Pharmacokinetics).

Table 5 - Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Drug Interaction Studies or Predicted Interactions^β (Information in the Table Applies to Co-administration of PREVYMIS® and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated)

Legend: CT = Clinical Trial; T = Theoretical

Drugs without Clinically Significant Interactions with PREVYMIS®

There was no clinically relevant interaction when PREVYMIS® was co-administered with itraconazole, a P-gp/BCRP inhibitor.

There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, and acyclovir, an OAT3 substrate, following co-administration with PREVYMIS® in clinical studies (see below).

The interaction between letermovir and the following drugs was evaluated in clinical studies: mycophenolate mofetil, fluconazole, posaconazole, and oral combinations of ethinyl estradiol/levonorgestrel. No dose adjustments are needed when PREVYMIS® is used with these drugs.

Drug Interaction Studies

Drug interaction studies were performed in healthy subjects with PREVYMIS® and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions (see Table 6 and Table 7).

In vitro results indicate that letermovir is a substrate of OATP1B1/3, P-gp, UGT1A1, and UGT1A3. Inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations. If PREVYMIS® is co-administered with cyclosporine (a potent OATP1B1/3 inhibitor), the recommended dose of PREVYMIS® is 240 mg once daily (see 4.2 Recommended Dose and Dosage Adjustment). Changes in letermovir plasma concentrations due to inhibition of P-gp/BCRP by itraconazole were not clinically relevant. Inhibition of UGTs is not anticipated to have a clinically relevant effect on letermovir plasma concentrations. Induction of drug enzymes (e.g., UGTs) and/or transporters (e.g., P-gp) by rifampin may result in clinically relevant decreases in letermovir plasma concentrations; therefore, co-administration of strong and moderate inducers with letermovir is not recommended (see Effect of Other Drugs on PREVYMIS®, Table 5, and Table 6). Although CYP3A, CYP2D6 and CYP2J2 were identified as enzymes capable of mediating the metabolism of letermovir in vitro, oxidative metabolism is considered to be a minor elimination pathway based on in vivo human data.

Letermovir is a time-dependent inhibitor and inducer of CYP3A in vitro. Co-administration of PREVYMIS® with midazolam resulted in increased exposure of midazolam, indicating that the net effect of letermovir on CYP3A is moderate inhibition (see Table 5). Based on these results, co-administration of PREVYMIS® with CYP3A substrates may increase the plasma concentrations of the CYP3A substrates (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS, 9.4 Drug-Drug Interactions, and Table 5). Letermovir is a reversible inhibitor of CYP2C8 in vitro. Physiologically based pharmacokinetic modeling predicts an increase in plasma concentrations of CYP2C8 substrates when co-administered with PREVYMIS® (see Table 5 in 9.4 Drug-Drug Interactions). Co-administration of PREVYMIS® reduced the exposure of voriconazole, most likely due to the induction of voriconazole elimination pathways, CYP2C9 and CYP2C19. Co-administration of PREVYMIS® with CYP2C9 and CYP2C19 substrates may decrease the plasma concentrations of the CYP2C9 and CYP2C19 substrates (see Table 5 in 9.4 Drug-Drug Interactions). Letermovir is an inducer of CYP2B6 in vitro; the clinical relevance is unknown.

Letermovir inhibited efflux transporters P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), OAT3, and hepatic uptake transporter OATP1B1/3 in vitro. Co-administration of PREVYMIS® with substrates of OATP1B1/3 transporters (e.g., atorvastatin, a known substrate of CYP3A, OATP1B1/3, and potentially BCRP) may result in a clinically relevant increase in plasma concentrations of OATP1B1/3 substrates (see Table 5 in 9.4 Drug-Drug Interactions). There were no clinically relevant changes in plasma concentrations of digoxin, a P-gp substrate, or acyclovir, an OAT3 substrate, following co-administration with PREVYMIS® in clinical studies (see Table 7). The effect of letermovir on BCRP, BSEP, and MRP2 substrates was not evaluated in clinical studies; the clinical relevance is unknown.

Table 6 - Drug Interactions: Changes in Pharmacokinetics of Letermovir in the Presence of Co-Administered Drug

Table 7 - Drug Interactions: Changes in Pharmacokinetics for Co-Administered Drug in the Presence of Letermovir or Co-Administered Letermovir

9.5 Drug-Food Interactions

Food increases peak levels (C_max) but not exposure (AUC_T) of PREVYMIS® following administration with a high fat, high calorie meal (see 4.1 Dosing Considerations and 10.3 Pharmacokinetics, Absorption, Effect of Food).

9.6 Drug-Herb Interactions

Co-administration of PREVYMIS® with St. John’s wort (Hypericum perforatum) may decrease plasma concentrations of letermovir.

Co-administration of PREVYMIS® and St. John’s wort is not recommended (see Table 5 in 9.4 Drug-Drug Interactions).

9.7 Drug-Laboratory Test Interactions

Interactions with clinical laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

PREVYMIS® is an antiviral drug against CMV (see 15 MICROBIOLOGY).

10.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of letermovir on doses up to 960 mg given IV on the QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg oral) 4-period crossover thorough QT trial in 38 healthy subjects. Letermovir did not prolong QTc to any clinically relevant extent following the 960 mg IV dose with plasma concentrations approximately 2-fold higher than the 480 mg IV dose.

10.3 Pharmacokinetics

The pharmacokinetics of letermovir have been characterized following oral and IV administration in healthy subjects and HSCT recipients and following oral administration in kidney transplant recipients.

Healthy Subjects

Letermovir exposure increased in a greater than dose-proportional manner with both oral or IV administration following single and multiple doses of 240 mg and 480 mg. Letermovir was absorbed rapidly with a median time to maximum plasma concentration (T_max) of 1.5 to 3.0 hours and declined in a biphasic manner. The geometric mean steady-state AUC and C_max values were 71,500 ng•hr/mL and 13,000 ng/mL, respectively, with 480 mg once daily oral PREVYMIS®. The post-absorption plasma concentration-time profile of letermovir following oral administration was similar to the profile observed with IV dosing. Letermovir clearance (CL) reached steady-state in 9 to 10 days with an accumulation ratio of 1.22 for AUC and 1.03 for C_max.

HSCT Recipients

Letermovir AUC was estimated using population pharmacokinetic analyses using Phase 3 data (see Table 8). Differences in exposure across treatment regimens are not clinically relevant; efficacy was consistent across the range of exposures observed in P001.

Table 8 - Letermovir AUC (ng•hr/mL) Values in HSCT Recipients

Kidney Transplant Recipients

Letermovir AUC was estimated using population pharmacokinetic analysis using Phase 3 data (see Table 9). Efficacy was consistent across the range of exposures observed in P002.

Table 9 - Letermovir AUC (ng•hr/mL) Values in Kidney Transplant Recipients

Absorption

In healthy subjects, absolute bioavailability of letermovir was estimated to be approximately 94% over the dose range 240 mg to 480 mg based on population pharmacokinetic analyses. In HSCT recipients, bioavailability of letermovir was estimated to be approximately 35% with 480 mg once daily oral PREVYMIS® administered without cyclosporine. The inter-individual variability for bioavailability was estimated to be approximately 37%. In kidney transplant recipients, bioavailability of letermovir was estimated to be approximately 60% with 480 mg once daily oral PREVYMIS® administered without cyclosporine.

Effect of Cyclosporine

In HSCT recipients, co-administration of cyclosporine increased plasma concentrations of letermovir. Bioavailability of letermovir was estimated to be approximately 85% with 240 mg once daily oral PREVYMIS® co-administered with cyclosporine. If PREVYMIS® is co-administered with cyclosporine, the recommended dose of PREVYMIS® is 240 mg once daily (see 4.2 Recommended Dose and Dosage Adjustment).

Effect of Food

Relative to administration under fasting conditions, oral administration of a single 480 mg dose of PREVYMIS® 480 mg tablets with a standard high fat, high calorie meal resulted in no significant effect on overall exposure (AUC_T) of letermovir and an increase in peak levels (C_max) of approximately 30%. The increase in C_max is not clinically relevant (see 4.1 Dosing Considerations and 9.5 Drug-Food Interactions).

Distribution:

Based on population pharmacokinetic analyses, the mean steady-state volume of distribution is estimated to be 45.5 L following IV administration in HSCT recipients.

Letermovir is extensively bound (98.7%) to human plasma proteins in vitro. Blood to plasma partitioning of letermovir is 0.56 and independent of the concentration range (0.1 to 10 mg/L) evaluated in vitro.

In preclinical distribution studies, letermovir is distributed to organs and tissues with the highest concentrations observed in the gastrointestinal tract, bile duct and liver and low concentrations in the brain.

In pregnant rats, letermovir was able to cross the placenta (see 7.1 Special Populations, Pregnant Women).

Metabolism:

The majority of drug-related component in plasma is unchanged parent (96.6%). No major metabolites are detected in plasma. Letermovir is partly eliminated by glucuronidation mediated by UGT1A1/1A3.

Elimination

The mean apparent terminal half-life for letermovir is approximately 12 hours with 480 mg IV PREVYMIS® in healthy subjects.

Excretion

Based on population pharmacokinetic analyses, letermovir steady-state CL is estimated to be 4.84 L/hr following IV administration in HSCT recipients. The inter-individual variability for CL is estimated to be 24.6%.

After oral administration of radio-labeled letermovir, 93.3% of radioactivity was recovered in feces. The majority of drug was excreted as unchanged parent with a minor amount (6% of dose) as an acyl-glucuronide metabolite in feces. Urinary excretion of letermovir was negligible (<2% of dose).

Special Populations and Conditions

• Pediatrics: The pharmacokinetics of letermovir in pediatric patients less than 18 years of age have not been evaluated.
• Geriatrics: Based on population pharmacokinetic analyses, there is no effect of age on letermovir pharmacokinetics. No dose adjustment is required based on age.
• Sex: Based on population pharmacokinetic analyses, there is no difference in letermovir pharmacokinetics in females compared to males.
• Genetic Polymorphism: The impact of genetic variants in the OATP1B1 gene SLCO1B1 (rs4149056, rs2306283, rs4149032) and UGT1A1 (rs4148323 and the promoter TA repeat variants) on the pharmacokinetics of letermovir was evaluated in 299 study participants. There was no clinically relevant impact of these variants on letermovir exposures.
• Ethnic Origin: Based on Phase 1 population pharmacokinetic analyses in HSCT recipients, letermovir AUC is estimated to be 33.2% higher in Asians compared to Whites. This change is not clinically relevant.

• Hepatic Insufficiency: Letermovir AUC was approximately 1.6- and 3.8-fold higher in subjects with moderate (Child-Pugh Class B [CP-B], score of 7-9) and severe (Child-Pugh Class C [CP-C], score of 10-15) hepatic impairment, respectively, compared to healthy subjects. The changes in letermovir exposure in subjects with moderate hepatic impairment are not clinically relevant.

  Clinically relevant increases in letermovir exposure are anticipated in patients with severe hepatic impairment.

• Renal Insufficiency:

  • Clinical Study in a Renally Impaired Population

Letermovir AUC was approximately 1.9- and 1.4-fold higher in subjects with moderate (eGFR greater than or equal to 30 to 59 mL/min/1.73m²) and severe (eGFR less than 30 mL/min/1.73m²) renal impairment, respectively, compared to healthy subjects. The changes in letermovir exposure due to renal impairment are not clinically relevant.

• Post-kidney Transplant

Based on population pharmacokinetic analysis, letermovir AUC was approximately 1.1-, 1.3- and 1.4-fold higher in subjects with mild (CrCl greater than or equal to 60 to less than 90 mL/min), moderate (CrCl greater than or equal to 30 to less than 60 mL/min) and severe (CrCl greater than or equal to 15 to less than 30 mL/min) renal impairment, respectively, compared to subjects with CrCl greater than or equal to 90 mL/min. These changes are not clinically relevant.

• Combined Renal and Hepatic Insufficiency: Clinically relevant increases in letermovir exposure are anticipated in patients with moderate hepatic impairment combined with moderate or severe renal impairment.
• Obesity: Based on Phase 1 population pharmacokinetic analyses, letermovir AUC is estimated to be 18.7% lower in subjects weighing 80-100 kg compared to subjects weighing 67 kg. Based on population pharmacokinetic analysis in kidney transplant recipients, letermovir AUC is estimated to be 26% lower in subjects weighing greater than 80 kg compared to subjects weighing less than or equal to 80 kg. These changes are not clinically relevant.

11 STORAGE, STABILITY AND DISPOSAL

Tablets and solution for injection:

Store PREVYMIS® tablets in the original package until use.

Store PREVYMIS® tablets at room temperature (15°C to 30°C).

Store PREVYMIS® for injection vials at 15°C to 25°C. Store in the original carton to protect from exposure to light.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: letermovir

Chemical name: (4S)-2-{8-Fluoro-2-[4-(3- methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

Molecular formula and molecular mass: C₂₉H₂₈F₄N₄O₄, 572.55

Structural formula:

Physicochemical properties: Letermovir drug substance (DS) is amorphous powder, with two pKa values at 3.6 and 7.1. Letermovir exists predominantly in the zwitterion form between pH 4 and pH 7 with a low intrinsic solubility of approximately 0.3 mg/mL. Solubility increases above pH 7 to 7.7 mg/mL and 25.5 mg/mL at pH 8 and pH 9, respectively.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Adult CMV-seropositive Recipients [R+] of an Allogeneic Hematopoietic Stem Cell Transplant (HSCT):

A phase III study to evaluate the safety and efficacy of PREVYMIS® in the prevention of clinically significant CMV infection in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. A summary of trial design and demographics is presented in Table 10:

Table 10 - Summary of Trial Design and Patient Demographics for the Phase III Trial in HSCT Recipients (P001)

Prophylaxis Through Week 14 (~100 days) Post-HSCT

Subjects were randomized (2:1) to receive either PREVYMIS® or placebo. Randomization was stratified by investigational site and risk level for CMV reactivation at the time of study entry. Study drug was initiated after HSCT (Day 0-28 post-HSCT) and continued through Week 14 post-HSCT. Subjects were monitored through Week 24 post-HSCT for the primary efficacy endpoint.

At baseline, 31% of subjects were in the high risk stratum as defined by one or more of the following criteria: Human Leukocyte Antigen (HLA)-related (sibling) donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR, haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; Grade 2 or greater Graft-Versus-Host Disease (GVHD), requiring systemic corticosteroids. The remaining 69% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum.

Clinically Significant CMV Infection

The primary efficacy endpoint of P001 was the incidence of clinically significant CMV infection through Week 24 post-HSCT. Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive therapy (PET) based on documented CMV viremia (using the Roche COBAS^* AmpliPrep/COBAS TaqMan^* assay, Lower Limit of Quantification (LLoQ) is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the study prior to Week 24 post-HSCT or had a missing outcome at Week 24 post-HSCT were counted as failures.

PREVYMIS® demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as shown in Table 11. The estimated treatment difference of -23.5% was statistically significant (one-sided p-value <0.0001).

Table 11- P001 Efficacy Results in HSCT Recipients (NC=F Approach, FAS Population)

At Week 14 post-HSCT, the Kaplan-Meier (K-M) event rate for clinically significant CMV infection was 6.8% in the PREVYMIS® group compared to 41.3% in the placebo group. At Week 24 post-HSCT, the K-M event rate for clinically significant CMV infection was 18.9% in the PREVYMIS® group compared to 44.3% in the placebo group (nominal two-sided stratified log-rank p-value<0.0001). Factors associated with clinically significant CMV infection between Week 14 and Week 24 post-HSCT among PREVYMIS®-treated subjects included high risk for CMV reactivation at baseline, having GVHD, and steroid use at any time after randomization.

Of the 373 subjects treated with PREVYMIS® in P001, 56 (15.0%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects.

Efficacy consistently favored PREVYMIS® across subgroups including low and high risk strata for CMV reactivation, stem cell source, donor mismatch, haploidentical transplant, conditioning regimens, and concomitant immunosuppressive regimens.

Mortality

The K-M event rate for all-cause mortality in the letermovir vs. placebo groups was 12.1% vs. 17.2% at Week 24 post-HSCT, and 23.8% vs. 27.6% at Week 48 post-HSCT.

The K-M event rate for CMV-related mortality (defined as death due to any reason in patients with clinically significant CMV infection [primary endpoint]) in the letermovir vs. placebo group was 0.7% vs. 9.1% at Week 24 post-HSCT (nominal two-sided stratified log-rank p-value < 0.0001), and 3.6% vs. 16.0% at Week 48 post-HSCT (nominal two-sided stratified log rank p-value < 0.0001).

Prophylaxis From Week 14 (~100 days) Through Week 28 (~200 days) Post-HSCT

The efficacy of extending PREVYMIS® prophylaxis from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT in patients at risk for late CMV infection and disease was assessed in adult CMV-seropositive recipients [R+] of an allogeneic HSCT. Eligible subjects who completed PREVYMIS® prophylaxis through ~100 days post-HSCT were randomized (2:1) to receive PREVYMIS® or placebo from Week 14 through Week 28 post-HSCT. Subjects were monitored through Week 28 post-HSCT for the primary efficacy endpoint with continued off-treatment follow-up through Week 48 post-HSCT.

At study entry, all subjects had risk factors for late CMV infection and disease, with 64% having two or more risk factors. The risk factors included: HLA-related (sibling) donor with at least one mismatch at one of the following three HLA-gene loci: HLA-A, -B or –DR; haploidentical donor; unrelated donor with at least one mismatch at one of the following four HLA-gene loci: HLA-A, -B, -C and -DRB1; use of umbilical cord blood as stem cell source; use of ex vivo T-cell-depleted grafts; receipt of anti-thymocyte globulin; receipt of alemtuzumab; use of systemic prednisone (or equivalent) at a dose of ≥1 mg/kg of body weight per day.

Clinically Significant CMV Infection

The primary efficacy endpoint of P040 was the incidence of clinically significant CMV infection through Week 28 post-HSCT. Clinically significant CMV infection was defined as the occurrence of either CMV end-organ disease, or initiation of anti-CMV PET based on documented CMV viremia and the clinical condition of the subject.

The Observed Failure (OF) approach was used, where subjects who discontinued prematurely from the study without viremia or were missing data at the timepoint were not counted as failures. The number of subjects who discontinued from the study before Week 28 without viremia was 14 (9.7%) in the PREVYMIS arm and 0 in the placebo arm. The number of subjects with a missing outcome in the Week 28 visit window was 3 (2.1%) in the PREVYMIS arm and 4 (5.4%) in the placebo arm, none had prior viremia.

PREVYMIS® demonstrated superior efficacy over placebo in the analysis of the primary endpoint, as shown in Table 12. The estimated treatment difference of -16.1% was statistically significant (one-sided p-value=0.0005). Efficacy consistently favored PREVYMIS® across subgroups based on subject characteristics (age, gender, race) and risk factors for late CMV infection and disease.

Table 12. P040 Efficacy Results in HSCT Recipients at Risk for Late CMV Infection and Disease (OF Approach, FAS Population)

Among subjects in the PREVYMIS group, the cumulative rate of clinically significant CMV infection increased from 1.6% at the end of prophylaxis (Week 28) to 15.6% at Week 38. In the placebo group, the cumulative rate of clinically significant CMV infection increased from 17.6% at Week 28 to 19.0% at Week 38. There were no additional cases of clinically significant CMV infection in either group between Weeks 38 and 48.

Adult CMV-seronegative Recipients of a Kidney Transplant from a CMV-seropositive Donor [D+/R-]

A phase III study to evaluate the efficacy of PREVYMIS® prophylaxis as a preventive strategy for CMV disease in adult kidney transplant recipients at high risk [D+/R-]. A summary of trial design and demographics is presented in Table 13:

Table 13 - Summary of Trial Design and Patient Demographics for the Phase III Trial in Kidney Transplant Recipients (P002)

Subjects were randomized (1:1) to receive either PREVYMIS® or valganciclovir. PREVYMIS® was given concomitantly with acyclovir for herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis. Subjects randomized to the valganciclovir group were given a placebo to acyclovir. Randomization was stratified by the use or nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction. Study drug was initiated between Day 0 and Day 7 post-kidney transplant and continued through Week 28 (~200 days) post-transplant. Subjects were monitored through Week 52 post-transplant.

CMV Disease

The primary efficacy endpoint of P002 was the incidence of CMV disease (CMV end-organ disease or CMV syndrome, confirmed by an independent adjudication committee) through Week 52 post-transplant. The Observed Failure (OF) approach was used, where subjects who discontinued prematurely from the study for any reason or were missing data at the timepoint were not considered failures. The number of subjects who discontinued from the study before Week 52 was 32 (11.1%) in the PREVYMIS® group and 28 (9.4%) in the valganciclovir group. The number of subjects with a missing outcome in the Week 52 visit window was 24 (8.3%) in the PREVYMIS® group and 25 (8.4%) in the valganciclovir group.

Based on a non-inferiority margin of 10%, PREVYMIS® demonstrated non-inferiority to valganciclovir in the analysis of the primary endpoint, as shown in Table 14.

Table 14: P002 Efficacy Results in Kidney Transplant Recipients (OF Approach, FAS Population)

Efficacy was comparable across all subgroups, including the use/nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction.

No subjects in the PREVYMIS® group experienced CMV disease through Week 28 post-transplant compared with 5 subjects in the valganciclovir group.

15 MICROBIOLOGY

Mechanism of Action

Letermovir inhibits the CMV DNA terminase complex, which is required for viral DNA replication. Biochemical characterization and electron microscopy demonstrated that letermovir affects the formation of proper unit length genomes and interferes with virion maturation.

Antiviral Activity

The median EC₅₀ value of letermovir against a collection of clinical CMV isolates in a cell-culture model of infection was 2.1 nM (range = 0.7 nM to 6.1 nM, n = 74). There was no significant difference in EC₅₀ value by CMV gB genotype (n=70).

Viral Resistance

In Cell Culture

The CMV genes UL51, UL56, and UL89 encode subunits of CMV DNA terminase. CMV mutants with reduced susceptibility to letermovir have been selected in cell culture, and the substitutions map to pUL51 (P91S, A95V), pUL56 (C25F, S229F,V231A, V231L, N232Y, V236A, V236L, V236M, E237D, L241P, T244K, T244R, L254F, L257F, L257I, K258E, F261C, F261L, F261S, Y321C, C325F, C325R, C325W, C325Y, L328V, M329T, A365S, N368D, R369G, R369M, R369S), and pUL89 (N320H, D344E). EC₅₀ values for recombinant CMV mutants expressing these substitutions are 1.6- to 9300-fold higher than those for the wild-type reference virus. EC₅₀ ratios of >3000 are interpreted as absolute letermovir resistance, because viral yield reduction occurs at visibly cytotoxic letermovir concentrations.

In Clinical Studies

In a Phase 2b trial evaluating letermovir doses of 60, 120, or 240 mg/day or placebo for up to 84 days in 131 HSCT recipients, DNA sequence analysis of a select region of UL56 (amino acids 231 to 369) was performed on samples obtained from 12 letermovir-treated subjects who experienced prophylaxis failure and for whom samples were available for analysis. One subject (who received 60 mg/day) had a letermovir resistant genotypic variant (GV) (V236M).

In a Phase 3 trial (P001), DNA sequence analysis of the entire coding regions of UL56 and UL89 was performed on samples obtained from 50 letermovir-treated subjects who experienced prophylaxis failure and for whom samples were available for analysis. A total of 4 letermovir resistance-associated substitutions all mapping to pUL56 were detected in 3 subjects as follows: V236M, C325W and R369T, and E237G, respectively.

In a Phase 3 trial (P002), DNA sequence analysis of the entire coding regions of UL51, UL56 and UL89 was performed on samples obtained from 52 letermovir-treated subjects who experienced CMV disease or who discontinued early with CMV viremia. There were no letermovir resistance-associated substitutions detected above the validated assay limit of 5%.

In a Phase 3 trial (P040), DNA sequence analysis of the entire coding regions of UL51, UL56 and UL89 was performed on samples obtained from 32 subjects (regardless of treatment group) who experienced prophylaxis failure or who discontinued early with CMV viremia. There were no letermovir resistance-associated substitutions detected above the validated assay limit.

Cross Resistance

Cross resistance is not likely with drugs outside of this class. Letermovir is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors (ganciclovir, cidofovir, and foscarnet). A panel of recombinant CMV strains with substitutions conferring resistance to letermovir was fully susceptible to cidofovir, foscarnet and ganciclovir with the exception of a recombinant strain with the pUL56 E237G substitution which confers a 2.1-fold reduction in ganciclovir susceptibility relative to wild-type.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: Testicular toxicity was noted only in rats at systemic exposures (AUC) ≥3-fold the exposures in humans at the recommended human dose (RHD). This toxicity was characterized by seminiferous tubular degeneration, and oligospermia and cell debris in the epididymides, with decreased testicular and epididymides weights. The No-Observed Adverse Effect Level (NOAEL) for testicular toxicity in rats was observed at exposures (AUC) in rats similar to the exposures in humans at the RHD. This testicular toxicity appears to be species-specific; testicular toxicity was not observed in mice and monkeys at the highest doses tested at exposures up to 4-fold and 2-fold, respectively, the exposures in humans at the RHD. The relevance to humans is unknown (see 8.3 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data).

Carcinogenicity: A 6-month oral carcinogenicity study in rasH2 transgenic (Tg.rasH2) mice showed no evidence of human-relevant tumorigenesis up to the highest doses tested, 150 mg/kg/day approximately the same AUC in humans at the RHD) and 300 mg/kg/day (approximately 2-fold the AUC in humans at the RHD) in males and females, respectively.

Genotoxicity: Letermovir was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis assays, chromosomal aberration in Chinese Hamster Ovary cells, and in an in vivo mouse micronucleus study.

Reproductive and Developmental Toxicology:

Reproduction

In the fertility and early embryonic development studies in the rat, there were no effects of letermovir on female fertility at the highest dose tested, 240 mg/kg/day (approximately 5-fold the AUC in humans at the RHD). In male rats, reduced sperm concentration, reduced sperm motility, and decreased fertility were observed at systemic exposures ≥ 3-fold the AUC in humans at the RHD (see General Toxicity).

Development

In pregnant rats, maternal toxicity (including decrease in body weight gain) was noted at the highest dose of 250 mg/kg/day (approximately 11-fold the AUC at the RHD); in the offspring, decreased fetal weight with delayed ossification, slightly edematous fetuses, and increased incidence of shortened umbilical cords and of variations and malformations in the vertebrae, ribs, and pelvis were observed. No maternal or developmental effects were noted up to the dose of 50 mg/kg/day (approximately 2.5-fold the AUC at the RHD).

In pregnant rabbits, maternal toxicity (including mortality and abortions) was noted at the highest dose of 225 mg/kg/day (approximately 2-fold the AUC at the RHD); in the offspring, an increased incidence of malformations and variations in the vertebrae and ribs were observed. No maternal or developmental effects were noted up to the dose of 75 mg/kg/day (at less than the AUC at the RHD).

In the pre- and post-natal developmental study, no developmental toxicity was observed up to the highest exposure of 180 mg/kg/day (2-fold the AUC at the RHD).

Lactation

No effects of letermovir on growth and postnatal development were observed in nursing rat pups at the highest dose tested (at 2-fold the AUC at the RHD) (see 7.1 Special Populations, Pregnant Women).