Prevymis Drug Information

Generic name: LETERMOVIR

Cytomegalovirus DNA Terminase Complex Inhibitor [EPC]

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Uses of Prevymis

CMV Prophylaxis in Hematopoietic Stem Cell Transplant (HSCT) Recipients

PREVYMIS ® is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT).

CMV Prophylaxis in Kidney Transplant Recipients

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative ).

Dosage & Administration of Prevymis

30 kg and above480 mg
15 kg to less than 30 kg240 mg
7.5 kg to less than 15 kg120 mg
6 kg to less than 7.5 kg80 mg

Side Effects of Prevymis

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. Adult CMV-seropositive Recipients 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) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-HSCT. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.

Cardiac Adverse Events The cardiac adverse event rate was higher 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% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity. Common Adverse Events The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 8. Table 8: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS-Treated HSCT Recipients at a Frequency at least 2% Greater than Placebo Adverse Events PREVYMIS (N=373) Placebo (N=192) nausea 27% 23% diarrhea 26% 24% vomiting 19% 14% peripheral edema 14% 9% cough 14% 10% headache 14% 9% fatigue 13% 11% abdominal pain 12% 9% Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs. 12% of placebo subjects). The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects. Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.

Laboratory Abnormalities Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in Table 9. Table 9: Trial P001 Selected Laboratory Abnormalities PREVYMIS N=373 Placebo N=192 Absolute neutrophil count (cells/μL) < 500 19% 19% 500 – < 750 4% 7% 750 – < 1000 8% 9% Hemoglobin (g/dL) < 6.5 2% 1% 6.5 – < 8.0 14% 15% 8.0 – < 9.5 41% 43% Platelets (cells/μL) < 25000 27% 21% 25000 – < 50000 17% 18% 50000 – < 100000 20% 30% Serum creatinine (mg/dL) > 2.5 2% 3% > 1.5 – 2.5 17% 20% The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm 3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group. 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. Adverse events were those reported while subjects were on study drug or within two weeks of study drug completion/discontinuation. The most commonly reported adverse events in P040 were similar to those reported in P001. Study drug was discontinued due to an adverse event in 5% of PREVYMIS subjects and 1% of placebo subjects.

The cardiac adverse event rate was 4% in the PREVYMIS and placebo groups. The rates of hematologic laboratory abnormalities were comparable in the PREVYMIS and placebo groups. Serum creatinine abnormalities > 1.5 mg/dL occurred in 15% of PREVYMIS and 8% of placebo subjects.

Adult Kidney Transplant Recipients 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. Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation. In these subjects, diarrhea was reported in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir (PREVYMIS, 32%; valganciclovir, 29%). Study drug was discontinued due to an adverse event in 4% of PREVYMIS subjects and 14% of valganciclovir subjects.

The most frequently reported adverse events that led to study drug discontinuation were neutropenia (PREVYMIS, 1%; valganciclovir, 2%) and leukopenia (PREVYMIS, 1%; valganciclovir, 5%). Laboratory Abnormalities Selected laboratory abnormalities reported through Week 28 post-transplant are presented in Table 10. Table 10: Trial P002 Selected Laboratory Abnormalities PREVYMIS N=292 Valganciclovir N=297 Absolute neutrophil count (cells/μL) < 500 2% 7% 500 – < 750 1% 4% 750 – < 1000 1% 8% Total < 1000 5% 18% Hemoglobin (g/dL) < 6.5 2% 0% 6.5 – < 8.0 4% 5% 8.0 – < 9.5 29% 32% Total < 9.5 34% 37% Platelets (cells/μL) < 50000 0% 0% 50000 – < 100000 1% 3% Total < 100000 1% 3% Leukocytes (cells/μL) < 1000 1% 2% 1000 – < 2000 5% 19% 2000 – < 2500 4% 14% Total < 2500 10% 35% Serum creatinine (mg/dL) > 2.5 24% 22% > 1.5 – 2.5 49% 52% Total > 1.5 73% 73% Pediatric Recipients of an Allogeneic HSCT The safety of PREVYMIS was evaluated in 63 pediatric subjects aged 2 months to less than 18 years of age who received an allogeneic HSCT (P030). PREVYMIS was administered orally (tablet or pellet) or intravenously. The duration of PREVYMIS exposure ranged from 3 days to 102 days (median duration 84 days). The safety profile was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.

Warnings & Cautions for Prevymis

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

The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug . See Table 11 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.

Risks Associated with Hydroxypropyl Betadex Excipient in Intravenous Formulation Intravenous formulation of

PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and patients should be switched to oral PREVYMIS as soon as they are able to take oral medications. If possible, intravenous administration should not exceed 4 weeks.

In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. In adult patients with CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, closely monitor serum creatinine levels . Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. The active ingredient, letermovir, is not known to be associated with ototoxicity.

Drug Interactions with Prevymis

Potential for Other Drugs to Affect

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 (Table 11). Co-administration of PREVYMIS with 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 Table 11 ).

Potential for

PREVYMIS to Affect Other Drugs Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A . 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 (Table 11) . Letermovir is an inhibitor of OATP1B1/3 transporters. 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 (Table 11). 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 prescribing information for cyclosporine for information on drug interactions with cyclosporine.

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 11 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on adult studies conducted with PREVYMIS or are predicted drug interactions that may occur with PREVYMIS . Table 11: Potentially Significant Drug Interactions: Alteration in Dose May Be Recommended Based on Results from Adult Drug Interaction Studies or Predicted Interactions This table is not all inclusive. (Information in the Table Applies to Co-administration of PREVYMIS and the Concomitant Drug without Cyclosporine, Unless Otherwise Indicated) Concomitant Drug Class and/or Clearance Pathway: Drug Name Effect on Concentration ↓ =decrease, ↑ =increase Clinical Comments Anti-arrhythmic Agents amiodarone ↑ amiodarone Close clinical monitoring for adverse events related to amiodarone is recommended during co-administration.

Frequently monitor amiodarone concentrations when amiodarone is co-administered with PREVYMIS. Antibiotics nafcillin ↓ letermovir Co-administration of PREVYMIS and nafcillin is not recommended due to potential for loss of efficacy of PREVYMIS. Anticoagulants warfarin ↓ warfarin When PREVYMIS is co-administered with warfarin, frequently monitor International Normalized Ratio (INR) Refer to the respective prescribing information.. Anticonvulsants carbamazepine ↓ letermovir Co-administration of PREVYMIS and carbamazepine is not recommended due to potential for loss of efficacy of PREVYMIS. phenobarbital ↓ letermovir Co-administration of PREVYMIS and phenobarbital is not recommended due to potential for loss of efficacy of PREVYMIS. phenytoin ↓ letermovir ↓ phenytoin Co-administration of PREVYMIS and phenytoin is not recommended due to potential for loss of efficacy of PREVYMIS. Antidiabetic Agents Examples: glyburide, repaglinide, rosiglitazone ↑ glyburide ↑ repaglinide ↑ rosiglitazone When PREVYMIS is co-administered with glyburide, repaglinide, or rosiglitazone, frequently monitor glucose concentrations. When PREVYMIS is co-administered with cyclosporine, use of repaglinide is not recommended. Antifungals voriconazole These interactions have been studied . ↓ voriconazole If concomitant administration of voriconazole is necessary, closely monitor for reduced effectiveness of voriconazole.

Antimycobacterials rifabutin ↓ letermovir Co-administration of PREVYMIS and rifabutin is not recommended due to potential for loss of efficacy of PREVYMIS. rifampin ↓ letermovir Co-administration of PREVYMIS and rifampin is not recommended due to potential for loss of efficacy of PREVYMIS. Antipsychotics pimozide ↑ pimozide Co-administration is contraindicated due to risk of QT prolongation and torsades de pointes . thioridazine ↓ letermovir Co-administration of PREVYMIS and thioridazine is not recommended due to potential for loss of efficacy of PREVYMIS. Endothelin Antagonists bosentan ↓ letermovir Co-administration of PREVYMIS and bosentan is not recommended due to potential for loss of efficacy of PREVYMIS. Ergot Alkaloids ergotamine, dihydroergotamine ↑ ergotamine, dihydroergotamine Co-administration is contraindicated due to risk of ergotism . Herbal Products St. John's wort ( Hypericum perforatum ) ↓ letermovir Co-administration of PREVYMIS and St. John's wort is not recommended due to potential for loss of efficacy of PREVYMIS. HIV Medications efavirenz ↓ letermovir Co-administration of PREVYMIS and efavirenz is not recommended due to potential for loss of efficacy of PREVYMIS. etravirine ↓ letermovir Co-administration of PREVYMIS and etravirine is not recommended due to potential for loss of efficacy of PREVYMIS. nevirapine ↓ letermovir Co-administration of PREVYMIS and nevirapine is not recommended due to potential for loss of efficacy of PREVYMIS. HMG-CoA Reductase Inhibitors atorvastatin ↑ atorvastatin When PREVYMIS is co-administered with atorvastatin, do not exceed an atorvastatin dosage of 20 mg daily.

Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of atorvastatin is not recommended. pitavastatin, simvastatin ↑ HMG-CoA reductase inhibitors Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis . fluvastatin, lovastatin, pravastatin, rosuvastatin ↑ HMG-CoA reductase inhibitors When PREVYMIS is co-administered with these statins, a statin dosage reduction may be necessary.

Closely monitor patients for myopathy and rhabdomyolysis. When PREVYMIS is co-administered with cyclosporine, use of lovastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, refer to the statin prescribing information for specific statin dosing recommendations.

Immunosuppressants cyclosporine ↑ cyclosporine ↑ letermovir Decrease the dosage of PREVYMIS to 240 mg once daily in adult and pediatric patients 12 years of age and older . Dose adjustment may be required in pediatric patients less than 12 years of age . Frequently monitor cyclosporine whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of cyclosporine accordingly. sirolimus ↑ sirolimus When PREVYMIS is co-administered with sirolimus, frequently monitor sirolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of sirolimus accordingly. When PREVYMIS is co-administered with cyclosporine and sirolimus, refer to the sirolimus prescribing information for specific sirolimus dosing recommendations. tacrolimus ↑ tacrolimus Frequently monitor tacrolimus whole blood concentrations during treatment and after discontinuation of PREVYMIS and adjust the dose of tacrolimus accordingly. Proton Pump Inhibitors omeprazole ↓ omeprazole Clinical monitoring and dose adjustment may be needed. pantoprazole ↓ pantoprazole Clinical monitoring and dose adjustment may be needed.

Wakefulness-Promoting Agents modafinil ↓ letermovir Co-administration of PREVYMIS and modafinil is not recommended due to potential for loss of efficacy of PREVYMIS. CYP3A Substrates Examples: alfentanil, fentanyl, midazolam, and quinidine ↑ CYP3A substrate When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor. When PREVYMIS is co-administered with cyclosporine, the combined effect on CYP3A substrates may be similar to a strong CYP3A inhibitor. Refer to the prescribing information for dosing of the CYP3A substrate with a strong CYP3A inhibitor.

CYP3A substrates pimozide and ergot alkaloids are contraindicated .

Drugs without Clinically Significant Interactions with

PREVYMIS No clinically significant interactions were observed in adult clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, fluconazole, itraconazole, posaconazole, ethinyl estradiol, and levonorgestrel.

Pregnancy Safety for Prevymis

Pregnancy Risk Summary No adequate human data are available to establish whether PREVYMIS poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD). Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD). In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).

Pediatric Use of Prevymis

  • Pediatric Use The safety and effectiveness of PREVYMIS have been established for: Prophylaxis of CMV infection and disease in pediatric CMV-seropositive recipients of an allogeneic HSCT 6 months of age and older and weighing at least 6 kg, and Prophylaxis of CMV disease in pediatric kidney transplant recipients 12 years of age and older and weighing at least 40 kg who are at high risk.
  • HSCT Recipients: The use of PREVYMIS for prophylaxis of CMV infection and disease in pediatric recipients of an allogeneic HSCT is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data from pediatric patients in Trial P030. The safety and pharmacokinetic results were similar to those in adults.
  • Kidney Transplant Recipients: The use of PREVYMIS for prophylaxis of CMV disease in high-risk kidney transplant recipients 12 years of age and older and weighing at least 40 kg is supported by evidence from an adequate and well-controlled study in adults and safety data from pediatric HSCT recipients (Trial P030). Letermovir exposures are expected to be similar between adult and pediatric patients 12 years of age and older and weighing at least 40 kg. The safety and effectiveness of PREVYMIS have not been established for: HSCT recipients less than 6 months of age or weighing less than 6 kg, or Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.

Contraindications for Prevymis

  • is contraindicated in patients receiving pimozide or ergot alkaloids: Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes .
  • Ergot alkaloids: Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism . PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Concomitant administration of PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis .
  • PREVYMIS is contraindicated with: Pimozide. Ergot Alkaloids. Pitavastatin and simvastatin when co-administered with cyclosporine.

Overdosage Information for Prevymis

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

Clinical Studies of Prevymis

Overview of Clinical Studies

An overview of the trials contributing to the assessment of efficacy and safety of PREVYMIS in HSCT and kidney transplant recipients is provided in Table 17. Table 17: Trials Conducted with PREVYMIS Trial (NCT Number) Population Trial Arms (N) N represents the number of subjects treated. Duration of Prophylaxis Post-Transplant Efficacy Endpoint P001 (NCT02137772) Adult allogeneic HSCT recipients PREVYMIS Placebo Through Week 14 Clinically significant CMV infection through Week 24 post-HSCT P040 (NCT03930615) Adult allogeneic HSCT recipients at risk for late CMV infection and disease PREVYMIS Placebo Extension of prophylaxis from Week 14 through Week 28 Clinically significant CMV infection through Week 28 post-HSCT P002 (NCT03443869) Adult kidney transplant recipients PREVYMIS Valganciclovir Through Week 28 CMV disease through Week 52 post-kidney transplant P030 (NCT03940586) Pediatric allogeneic HSCT recipients PREVYMIS Through Week 14 Clinically significant CMV infection through Week 24 post-HSCT

Adult

CMV-seropositive Recipients of an Allogeneic Hematopoietic Stem Cell Transplant (Trial P001 and Trial P040) Prophylaxis Through Week 14 (~100 days) Post-HSCT (Trial P001) To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV infection or disease in transplant recipients at high risk for CMV reactivation, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, placebo-controlled Phase 3 Trial (P001, NCT02137772) in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT). Subjects were randomized (2:1) to receive either PREVYMIS at a dose of 480 mg once daily adjusted to 240 mg when co-administered with cyclosporine, 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 (at any time from Day 0 to Day 28 post-HSCT) and continued through Week 14 post-HSCT. Study drug was administered either orally or intravenously; the dose of PREVYMIS was the same regardless of the route of administration.

Subjects received CMV DNA monitoring weekly until post-HSCT Week 14 and then bi-weekly until post-HSCT Week 24, with initiation of standard-of-care CMV pre-emptive therapy if CMV viremia was considered clinically significant. Subjects had continued follow-up through Week 48 post-HSCT. Among the 565 treated subjects, 70 subjects were found to have CMV viremia prior to study drug initiation and were therefore excluded from the efficacy analyses. The efficacy population consisted of 325 subjects who received PREVYMIS (including 91 subjects who received at least one IV dose) and 170 who received placebo (including 41 subjects who received at least one IV dose). The IV formulation of PREVYMIS was used at investigators' discretion in subjects who were unable to take oral therapy (e.g., unable to tolerate oral intake). The median time to starting study drug was 8 days after transplantation.

Thirty-four percent (34%) of subjects were engrafted at baseline. The median age was 55 years (range: 18 to 76 years). 57% were male; 84% were White; 9% were Asian; 2% were Black or African American; and 5% were other (American Indian or Alaska Native, multiple, and missing). 7% were Hispanic or Latino; 89% not Hispanic or Latino; and 4% other (not reported, unknown, and missing). At baseline, 30% of all subjects had one or more of the following factors associated with increased risk for CMV reactivation (high risk stratum): Human Leukocyte Antigen (HLA)-related 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 70% of subjects did not meet any of these high risk stratum criteria and were therefore included in the low risk stratum.

Additionally, 48% of subjects received a myeloablative regimen, 51% were receiving cyclosporine, and 43% were receiving tacrolimus. The most common primary reasons for transplant were acute myeloid leukemia (38%), myelodysplastic syndrome (16%), and lymphoma (12%). Clinically Significant CMV Infection The primary efficacy endpoint of Trial P001 was the incidence of clinically significant CMV infection through Week 24 post-HSCT (prophylaxis failure). 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, LLoQ is 137 IU/mL, which is approximately 150 copies/mL) and the clinical condition of the subject. The protocol-specified guidance for CMV DNA thresholds for the initiation of PET during the treatment period was ≥ 150 copies/mL or > 300 copies/mL for subjects in the high and low risk strata, respectively.

From Week 14 through Week 24, the threshold was >300 copies/mL for both high and low risk strata subjects. The Non-Completer=Failure (NC=F) approach was used, where subjects who discontinued from the trial prior to Week 24 post-HSCT or had a missing outcome at Week 24 post-HSCT were counted as failures. Efficacy results from Trial P001 are shown in Table 18. Table 18: Trial P001 Incidence of Clinically Significant CMV Infection in HSCT Recipients (NC=F Approach, FAS Population) Through Week 24 Parameter PREVYMIS (N=325) Placebo (N=170) Note: FAS=Full analysis set; FAS includes randomized subjects who received at least one dose of study medication, and excludes subjects with detectable CMV DNA at baseline.

Approach to handling missing values: Non-Completer=Failure (NC=F) approach. With NC=F approach, failure was defined as all subjects who developed clinically significant CMV infection or prematurely discontinued from the study or had a missing outcome through Week 24 post-HSCT visit window. Proportion of subjects who failed prophylaxis 38% 61% Reasons for failures The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed.

Clinically significant CMV infection by Week 24 Through Week 14, 8% of subjects in the PREVYMIS group and 39% of subjects in the placebo group experienced clinically significant CMV infection. 18% 42% Initiation of PET based on documented CMV viremia 16% 40% CMV end-organ disease 2% 2% Discontinued from study before Week 24 Reasons for discontinuation included adverse event, death, lost to follow-up, physician decision, and withdrawal by subject. 17% 16% Missing outcome in Week 24 visit window 3% 3% Stratum-adjusted treatment difference (PREVYMIS-Placebo) 95% CI and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (high or low risk). Difference (95% CI) -23.5 (-32.5, -14.6) p-value <0.0001. Efficacy results were consistent across high and low risk strata for CMV reactivation. The time to clinically significant CMV infection is shown in Figure 1. Among subjects in the PREVYMIS group, the cumulative rate of clinically significant CMV infection increased from 6.8% at the end of prophylaxis (Week 14) to 18.9% at Week 24. In the placebo group, the cumulative rate of clinically significant CMV infection increased from 41.3% at Week 14 to 44.3% at Week 24. Figure 1: P001: Kaplan-Meier Plot of Time to Onset of Clinically Significant CMV Infection Through Week 24 Post-Transplant in HSCT Recipients (FAS Population) Post-hoc analysis demonstrated that among PREVYMIS-treated subjects, inclusion in the high risk stratum for CMV reactivation at baseline, occurrence of GVHD, and steroid use at any time after randomization may be associated with the development of clinically significant CMV infection between Week 14 and Week 24 post-HSCT. Figure 1 Mortality The Kaplan-Meier event rate for all-cause mortality in the PREVYMIS vs. placebo groups was 12% vs. 17% at Week 24 post-HSCT, and 24% vs. 28% at Week 48 post-HSCT. Prophylaxis From Week 14 (~100 days) Through Week 28 (~200 days) Post-HSCT (Trial P040) 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 a multicenter, double-blind, placebo-controlled Phase 3 trial (P040, NCT03930615) in adult CMV-seropositive recipients 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 received PREVYMIS at a dose of 480 mg once daily (adjusted to 240 mg when co-administered with cyclosporine) or placebo. Study drug was administered either orally or IV; the dose of PREVYMIS was the same regardless of the route of administration.

One subject received IV PREVYMIS for 2 days. Subjects were monitored through Week 28 post-HSCT for the primary efficacy endpoint with continued off-treatment follow-up through Week 48 post-HSCT. Among the 218 treated subjects, 144 subjects received PREVYMIS and 74 received placebo. The median age was 55 years (range: 20 to 74 years); 62% were male; 79% were white; 11% were Asian; 2% were Black; 1% were multiple races; 6% had missing race; and 10% were Hispanic or Latino.

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. The most common reasons for transplant were acute myeloid leukemia (42%), acute lymphocytic leukemia (15%), and myelodysplastic syndrome (11%). Clinically Significant CMV Infection The primary efficacy endpoint of Trial 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.

Efficacy results from Trial P040 are shown in Table 19. Efficacy was consistent across subgroups based on participant characteristics (age, gender, race) and risk factors for late CMV infection and disease. Table 19: Trial P040 Efficacy Results in HSCT Recipients at Risk for Late CMV Infection and Disease (OF Approach, FAS Population) Parameter PREVYMIS (~200 days PREVYMIS) (N=144) Placebo (~100 days PREVYMIS) (N=74) Approach to handling missing values: Observed Failure (OF) approach. With the OF approach, failure was defined as all subjects who developed clinically significant CMV infection or discontinued prematurely from the study with CMV viremia from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT. N = Number of subjects in each treatment group.

Failures The categories of failure are mutually exclusive and based on the hierarchy of categories in the order listed. 2.8% 18.9% Clinically significant CMV infection from Week 14 through Week 28 Clinically significant CMV infection was defined as CMV end-organ disease (proven or probable) or initiation of PET based on documented CMV viremia and the clinical condition of the subject. 1.4% 17.6% Initiation of PET based on documented CMV viremia 0.7% 14.9% CMV end-organ disease 0.7% 2.7% Discontinued from study with CMV viremia before Week 28 1.4% 1.4% Stratum-adjusted treatment difference (PREVYMIS (~200 days PREVYMIS)-Placebo (~100 days PREVYMIS)) The 95% CIs and p-value for the treatment differences in percent response were calculated using stratum-adjusted Mantel-Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (haploidentical donor yes or no). A one-sided p-value ≤0.0249 was used for declaring statistical significance. Difference (95% CI) -16.1 (-25.8, -6.5) p-value = 0.0005 The time to clinically significant CMV infection is shown in Figure 2. 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. Figure 2: Trial P040 Kaplan-Meier Plot of Time to Onset of Clinically Significant CMV Infection From Week 14 Through Week 48 Post-transplant in HSCT Recipients at Risk for Late CMV Infection and Disease (FAS Population) Figure 2

Adult

CMV-seronegative Recipients of a Kidney Transplant from a CMV-seropositive Donor (Trial P002) To evaluate PREVYMIS prophylaxis as a preventive strategy for CMV disease in kidney transplant recipients, the efficacy of PREVYMIS was assessed in a multicenter, double-blind, active comparator-controlled non-inferiority Phase 3 trial (P002, NCT03443869) in adult kidney transplant recipients at high risk. Subjects were randomized (1:1) to receive either PREVYMIS or valganciclovir. PREVYMIS was administered at a dose of 480 mg once daily (adjusted to 240 mg when co-administered with cyclosporine). PREVYMIS was given concomitantly with acyclovir.

Valganciclovir was given concomitantly with 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.

Study drug was administered either orally or IV; the dose of PREVYMIS was the same regardless of the route of administration. Three subjects received IV PREVYMIS for a mean duration of 1.7 days. Subjects were monitored through Week 52 post-transplant.

Among the 589 treated subjects, 292 subjects received PREVYMIS and 297 received valganciclovir. The median age was 51 years (range: 18 to 82 years); 72% were male; 84% were White; 9% were Black; 3% were multiple; 2% were Asian; 1% Alaskan native or American Indian; 17% were Hispanic or Latino; and 60% received a kidney from a deceased donor. The most common primary reasons for transplant were congenital cystic kidney disease (17%), hypertension (16%), and diabetes/diabetic nephropathy (14%). CMV Disease The primary efficacy endpoint of Trial 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 counted as failures. The number of subjects who discontinued from the study before Week 52 was 32 (11%) in the PREVYMIS arm and 28 (9%) in the valganciclovir arm. The number of subjects with a missing outcome in the Week 52 visit window was 24 (8%) in the PREVYMIS arm and 25 (8%) in the valganciclovir arm.

Efficacy results from Trial P002 are shown in Table 20. Table 20: Trial P002 Incidence of CMV Disease in Kidney Transplant Recipients (OF Approach, FAS Population) Through Week 52 Parameter PREVYMIS (N=289) Valganciclovir (N=297) Note: Approach to handling missing values: Observed failure (OF) approach. With OF approach, subjects who discontinued from the study before Week 52 or had a missing outcome in the Week 52 visit window were not counted as failures. CMV Disease CMV disease cases confirmed by an independent adjudication committee.

Through Week 52 10% 12% CMV Syndrome Defined as evidence of CMV in blood by viral isolation, rapid culture, antigenemia, or nucleic acid testing, and two or more of the following: 1) fever ≥38°C for at least 2 days, 2) new or increased malaise/fatigue, 3) leukopenia or neutropenia on two separate measurements at least 24 hours apart, 4) ≥5% atypical lymphocytes, 5) thrombocytopenia, 6) elevation of ALT or AST to 2x ULN. 8% 11% CMV End-organ Disease 2% <1% Stratum-adjusted Treatment Difference The 95% CIs for the treatment differences in percent response were calculated using stratum-adjusted Mantel- Haenszel method with the difference weighted by the harmonic mean of sample size per arm for each stratum (use/non-use of highly cytolytic, anti-lymphocyte immunotherapy during induction). (PREVYMIS – Valganciclovir) -1.4 (-6.5, 3.8) Based on a non-inferiority margin of 10%, PREVYMIS is non-inferior to valganciclovir. Efficacy was comparable across all subgroups, including the use/nonuse of highly cytolytic, anti-lymphocyte immunotherapy during induction. In an exploratory analysis of the incidence of CMV disease through Week 28 post-transplant, the difference (PREVYMIS – Valganciclovir) was -1.7% with 95% CI of (-3.4, 0.1). No subjects in the PREVYMIS group experienced CMV disease through Week 28 post-transplant (end of treatment period) compared with 5 subjects in the valganciclovir group.

Pediatric Recipients of an Allogeneic

HSCT (Trial P030) Sixty-three children 2 months to less than 18 years of age who had an allogeneic HSCT were enrolled in a multicenter, open-label, single-arm pharmacokinetic, safety and effectiveness study of PREVYMIS (P030, NCT03940586). Subjects received PREVYMIS daily either orally or intravenously for CMV prophylaxis within 28 days post-HSCT through Week 14 post-HSCT. The intravenous formulation was used for up to four weeks in subjects who were unable to take oral therapy. The daily doses of PREVYMIS were based on body weight. Among the 63 treated subjects, 8 were 2 months to less than 2 years of age, 27 were 2 to less than 12 years of age and 28 were 12 to less than 18 years of age.

The median age was 11 years; 70% were male; 70% were White; 14% were Asian; 5% were Black; and 22% were Hispanic or Latino. The efficacy analyses population consisted of 56 subjects who received at least one dose of study drug and had no detectable CMV DNA at baseline. The proportion of subjects who failed CMV prophylaxis through Week 24 post-HSCT was 25% (14 of the 56 subjects). Six subjects had initiation of pre-emptive therapy based on CMV viremia and 8 subjects discontinued from the study before Week 24. None of the subjects had CMV end-organ disease.

PREVYMIS is indicated for pediatric recipients of an allogeneic HSCT aged 6 months and older and weighing at least 6 kg.

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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