Summary Basis of Decision for Prevymis

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Prevymis is located below.

Recent Activity for Prevymis

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Prevymis

Updated:

2019-12-17

The following table describes post-authorization activity for Prevymis, a product which contains the medicinal ingredient letermovir. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

Drug Identification Numbers (DINs):

  • DIN 02469375 - 240 mg, letermovir, tablet, oral
  • DIN 02469383 - 480 mg, letermovir, tablet, oral
  • DIN 02469367 - 20 mg/mL (240 mg/12 mL), letermovir, solution, intravenous
  • DIN 02469405 - 20 mg/mL (480 mg/24 mL), letermovir, solution, intravenous

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
NC # 2270342019-04-23Issued NOL
2019-07-19
Submission filed as a Level II (120 day) Notifiable Change to update the PM with safety information. As a result of the NC, modifications were made to the Contraindications, Warnings and Precautions, and Drug Interactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 2210052018-10-31Issued NOL
2019-01-15
Submission filed as a Level II (120 day) Notifiable Change to update the PM with safety-related changes. As a result of the NC, modifications were made to the Drug Interactions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 2165372018-05-29Issued NOL
2018-09-12
The submission was filed as a Level II (90 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Contraindications; Drug Interactions; and Storage, Stability and Disposal sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02469375, 02469383, 02469367, 02469405) market notificationNot applicableDate of first sale:
2017-12-20
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations
NDS # 2041652017-04-10Issued NOC
2017-11-01
Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Prevymis

Date SBD issued: 2018-06-04

The following information relates to the new drug submission for Prevymis.

Letermovir
240 mg and 480 mg, tablet, oral
20 mg/mL (240 mg/vial and 480 mg/vial), solution, intravenous

Drug Identification Number (DIN):

  • DIN 02469375 - 240 mg, tablet
  • DIN 02469383 - 480 mg, tablet
  • DIN 02469367 - 20 mg/mL (240 mg/12 mL), solution
  • DIN 02469405 - 20 mg/mL (480 mg/24 mL), solution

Merck Canada Inc.

New Drug Submission Control Number: 204165

On November 1, 2017, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the drug product Prevymis.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Prevymis is favourable for the prophylaxis of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients (R+) of an allogeneic hematopoietic stem cell transplant (HSCT).

1 What was approved?

Prevymis, an antiviral agent, was authorized for the prophylaxis of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients (R+) of an allogeneic hematopoietic stem cell transplant (HSCT).

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.

Prevymis is contraindicated with pimozide and ergot alkaloids, drugs that are highly dependent on cytochrome P450 3A (CYP3A) for clearance and for which elevated plasma concentrations are associated with serious or life-threatening reactions. Due to inhibition of CYP3A by Prevymis, concomitant administration of Prevymis with pimozide may result in increased concentrations of pimozide, leading to QT prolongation and torsades de pointes. Concomitant administration of Prevymis with ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism.

Safety and efficacy of Prevymis have not been established in pediatric patients under 18 years of age.

Safety and efficacy were similar across older (≥65 years of age) and younger subjects in the Phase III trial in HSCT recipients.

Prevymis was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Prevymis (letermovir) is presented as a tablet (240 mg and 480 mg) and as a solution for injection (240 mg/12 mL and 480 mg/24 mL) supplied in single-dose vials.

In addition to the medicinal ingredient, the tablet contains colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and povidone 25. The tablet film-coating contains hypromellose 2910, iron oxide yellow, and (only for 480 mg tablets) iron oxide red, lactose monohydrate, titanium dioxide and triacetin. Carnauba wax is added as a polishing agent.

Each mL of the solution contains hydroxypropyl betadex (150 mg), sodium chloride (3.1 mg), sodium hydroxide (1.2 mg), and water for injection. The amount of sodium hydroxide may be adjusted to achieve a pH of approximately 7.5.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Prevymis Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Prevymis approved?

Health Canada considers that the benefit-risk profile of Prevymis is favourable for the prophylaxis of cytomegalovirus (CMV) infection in adult CMV-seropositive recipients (R+) of an allogeneic hematopoietic stem cell transplant (HSCT).

Human cytomegalovirus (CMV) is a beta herpesvirus which is a frequent pathogen in humans and is usually associated with asymptomatic infection, followed by a state of viral persistence or latency. After allogeneic HSCT, there is a higher risk of active CMV infection specifically because of the delayed recovery of T- and B-cell functions. Recipients of allogenic HSCT are at a greater risk of infection complications because of a longer time to achieve engraftment (prolonged neutropenia) and the added risk of graft versus host disease (GVHD). Thus, the rate by which immune functions recover after hematopoietic reconstitution significantly influences the incidence of CMV infection and disease following stem cell transplantation (SCT). In a minority of CMV-seropositive patients, CMV disease can occur before engraftment, leading to a very high mortality. T-cell depletion of the graft is associated with a high rate of CMV reactivation, a rapid onset of CMV-related symptoms, and a higher rate of fatal infections that may occur during the first 30 days after SCT.

After engraftment, severe combined quantitative and functional deficiencies in the T- and B-lymphocyte compartment persist in patients with allogeneic SCT. These deficiencies manifest as disorders in helper T-cell function and immunoglobulin synthesis, but also as an impaired cytotoxic T-cell response. During this period, active CMV infection occurs in approximately 60-70% of CMV-seropositive patients or CMV-seronegative patients who receive transplants from a seropositive donor. If no preventive measures are taken, the risk of developing CMV disease equals 20-30%.

Direct clinical effects of CMV infection in HSCT recipients include a wide spectrum of CMV disease manifestations, associated with considerable morbidity and mortality. Gastroenteritis is the most common clinical presentation in HSCT recipients. Other manifestations include pneumonia, hepatitis, retinitis, and encephalitis. Active CMV infection may be accompanied by myelosuppression and fever.

Indirect clinical effects of CMV infection include an increased risk of all-cause mortality, non-relapse mortality, GVHD, and opportunistic bacterial and invasive fungal infections.

Letermovir, the medicinal ingredient in Prevymis, is a novel, specific inhibitor of human CMV. It acts by inhibiting the CMV deoxyribonucleic acid (DNA) terminase complex, which cleaves newly synthesized CMV DNA into individual viral genomes. The novel mechanism of action of letermovir is distinct from currently authorized CMV agents, which inhibit the viral DNA polymerase. In cell culture models of infection, letermovir potently inhibited laboratory and clinical CMV isolates, including several strains resistant to other anti-CMV agents, with low nanomolar values of 50% effective concentration (EC50). There is no human homologue for this process; thus, the mechanism of action of Prevymis is highly specific suggesting a limited potential for mechanism-based toxicity. There is no known cross-resistance between Prevymis and currently authorized drugs for treatment of CMV.

Prevymis has been shown to prevent CMV infection in adult CMV-seropositive recipients (R+) of an allogeneic HSCT. The market authorization of Prevymis was based on efficacy and safety data derived from one randomized, double-blind, placebo-controlled Phase III trial (P001). Supportive data stemmed from 28 Phase I trials and two Phase II clinical trials (P019 and P020).

In the Phase III trial, 570 CMV-seropositive recipients (R+) of an allogeneic HSCT were randomized in a 2:1 ratio to receive either Prevymis (480 mg once daily, or 240 mg once daily if given concomitantly with cyclosporin) or matching placebo through Week 14 post-transplant. Patients could receive either oral or intravenous formulation, without any dose adjustment. A total of 565 patients received a study medication, 373 of whom received Prevymis. Efficacy and safety was evaluated through Week 24 post-transplant. The primary efficacy endpoint was the proportion of subjects with clinically significant CMV infection through Week 24 post-transplant, defined as the onset of CMV end-organ disease or initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the subject. Results of this trial demonstrate that Prevymis is superior to placebo in prevention of clinically significant CMV infection. Prophylaxis with Prevymis resulted in an approximately 40% relative risk reduction in clinically significant CMV infection compared to placebo. Prevymis was generally well tolerated. There was no evidence of myelotoxicity, nephrotoxicity or hepatotoxicity. The most commonly reported adverse events were GVHD, nausea, vomiting, diarrhea, pyrexia and rash. The incidence of these adverse events was comparable to the placebo group.

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; or significant decrease of concomitant drug plasma concentrations which may lead to reduced therapeutic effect of the concomitant drug. Therefore, appropriate contraindications and a Serious Drug Interactions box are included in the Prevymis Product Monograph. In addition, the Prevymis Product Monograph lists established or potentially significant drug interactions with recommendations for close monitoring and/or dose adjustments.

A Risk Management Plan (RMP) for Prevymis was submitted by Merck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Prevymis was accepted.

Prevymis has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Prevymis Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Prevymis?

The drug submission for Prevymis was reviewed under the Priority Review Policy on the basis that cytomegalovirus (CMV) infection following allogeneic hematopoietic stem cell transplant (HSCT) is a serious condition for which there is an unmet medical need, since it is not adequately managed by the current available options. Prevymis demonstrated a significant increase in efficacy with an improved benefit-risk profile over existing anti-CMV therapies in allogenic HSCT recipients.

Submission Milestones: Prevymis

Submission MilestoneDate
Pre-submission meeting:2017-01-25
Request for priority status
Filed:2017-02-24
Approval issued by Director, Bureau of Medical Sciences:2017-03-29
Submission filed:2017-04-10
Screening
Screening Acceptance Letter issued:2017-05-05
Review
Quality Evaluation complete:2017-10-31
Clinical Evaluation complete:2017-10-31
Review of Risk Management Plan complete:2017-10-25
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2017-10-31
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2017-11-01

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Letermovir, the medicinal ingredient in Prevymis, inhibits the cytomegalovirus (CMV) deoxyribonuclease acid (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.

The pharmacokinetics and initial safety/tolerability of letermovir have been characterized on the basis of 28 Phase I trials conducted in healthy adults (225 males and 541 females) and 6 population pharmacokinetic studies. The clinical pharmacological data support the use of Prevymis for the specified indication.

Following oral administration to healthy subjects, letermovir was rapidly absorbed with a median time to peak concentrations (tmax) of 0.75-2.25 hours and its absolute bioavailability was estimated to be approximately 94% in the dose range of 240 mg to 480 mg. Letermovir exhibited non-linear pharmacokinetics with greater than dose-proportional increases in exposure. No major metabolites were detected in plasma and the most prominent metabolite in feces was a glucuronide conjugate (~6% of dose). Letermovir was eliminated in feces (93%) mostly as unchanged parent compound, while the renal elimination was negligible (<2% of dose). The steady-state mean apparent half-life (t1/2) was approximately 12 hours. Steady state was achieved in 9-10 days.

A single supratherapeutic intravenous dose of 960 mg (two times the therapeutic dose) did not prolong the QTc interval to a clinically relevant extent. The effect of age, race/ethnicity, body weight, gender, or genetic variants in the OATP1B and UGT1A1 gene on letermovir exposure was estimated to be not clinically relevant. Moderate and severe hepatic impairment increased letermovir exposure up to 3.8-fold. Moderate and severe renal impairment also increased letermovir exposure. Fourteen drug-drug interaction studies assessed the effect of select immunosuppressants on the pharmacokinetics of letermovir, and the effect of letermovir on CYP3A and CYP2C9/2C19 substrates, and OATP1B1/3 substrates, when co-administered. The risks associated with drug interactions are addressed in the Prevymis Product Monograph. In general, Prevymis is safe and well tolerated in healthy subjects.

For further details, please refer to the Prevymis Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Prevymis for the prevention of CMV infection in adult CMV- seropositive recipients (R+) of an allogeneic HSCT was evaluated in a single randomized, double-blind, placebo-controlled, multi-site Phase III clinical trial (P001). In this trial, 570 CMV-seropositive recipients (R+) of an allogeneic hematopoietic stem cell transplant (HSCT) were randomized in a 2:1 ratio to receive either Prevymis (480 mg once daily, or 240 mg once daily if given concomitantly with cyclospoprine) or matching placebo through Week 14 post-transplant. Patients could receive either oral or intravenous formulation, without any dose adjustment. A total of 565 patients received a study medication, 373 of whom received Prevymis. Patients were monitored through Week 24 post-transplant for the primary efficacy endpoint.

The primary efficacy endpoint was the proportion of subjects with clinically significant CMV infection through Week 24 post-transplant. Clinically significant CMV infection was defined as the onset of CMV end-organ disease or initiation of anti-CMV pre-emptive therapy based on documented CMV viremia and the clinical condition of the patient.

Results of this trial demonstrate that Prevymis is superior to placebo in prevention of clinically significant CMV infection. The incidence of clinically significant CMV infection through Week 24 post-transplant was 37.5% in the Prevymis group compared to 60.6% in the placebo group (difference: -23.5%; one-sided p<0.0001). Prophylaxis with Prevymis resulted in a relative risk reduction of approximately 40% in clinically significant CMV infection as compared to placebo.

Indication

The New Drug Submission for Prevymis was filed by the sponsor with the following indication:

  • Prevymis (letermovir) is indicated for the prophylaxis of cytomegalovirus (CMV) infection or disease in adult CMV-seropositive recipients (R+) of an allogeneic hematopoietic stem cell transplant (HSCT).

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • 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).

For more information, refer to the Prevymis Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Prevymis was evaluated in the Phase III clinical trial P001 (described in the Clinical Efficacy section) in adult CMV- seropositive recipients (R+) of an allogeneic HSCT.

Prevymis was generally well tolerated in the clinical trial. Of the 373 patients who received Prevymis, drug related adverse events occurred in 63 (16.9%) patients, serious adverse events occurred in 193 (51.7%) patients, of which 3 events (delayed engraftment, pancytopenia, and thrombocytopenia) were considered to be drug related by the investigator, and 72 patients (19.3%) discontinued treatment because of adverse events. There was no evidence of myelotoxicity, nephrotoxicity or hepatotoxicity. The most commonly reported adverse events were graft versus host disease (GVHD), nausea, vomiting, diarrhea, pyrexia and rash. The incidence of these adverse events was comparable to the placebo group.

Appropriate warnings and precautions are in place in the approved Prevymis Product Monograph to address the identified safety concerns.

For more information, refer to the Prevymis Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The overall non-clinical evidence supports the development of letermovir, the medicinal ingredient in Prevymis, as an antiviral agent for prophylaxis of human cytomegalovirus (CMV) infection in adult CMV-seropositive recipients (R+) of an allogeneic HSCT.

In vitro pharmacodynamic studies demonstrated potent activity of letermovir against laboratory and clinical human CMV strains with 50% effective concentration (EC50) values ranging from 0.7 nM to 18 nM and very low cytotoxicity with selectivity index values of >10,000. Genotypic variants which showed resistance to letermovir carried mutations that mapped to the viral gene encoding the large subunit of the human CMV DNA terminase complex. The in vitro resistance profile of human CMV against letermovir was characterized and appropriately described in the Prevymis Product Monograph.

Letermovir showed additive interaction with all approved anti-CMV drugs. Furthermore, in vitro cross-resistance studies showed that letermovir retained full activity against mutants that confer resistance to one or more approved anti-CMV drugs (ganciclovir, cidofovir, foscarnet) and vice versa.

The in vitro pharmacokinetic interaction data indicated that letermovir can potentially have drug interactions via intestinal/liver efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), hepatic uptake transporters (OATP1B1 and OATP1B3), renal uptake transporters (OAT3), and cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8. These drug interactions were further investigated in clinical pharmacology studies or using physiologically based pharmacokinetic modelling, and they are presented in the Prevymis Product Monograph.

In safety pharmacology and toxicology studies, letermovir did not show any effects of concern on cardiovascular, respiratory, neurobehavioral and renal function at clinically relevant concentrations.

Testicular toxicity, resulting in reduced male fertility, was noted in rats in repeat-dose (oral administration for 13 weeks, as well as intravenous administration for 4 weeks) and fertility studies at exposures that were 7≥3 times the letermovir exposures in HSCT patients. However, given that these effects were not seen in other preclinical animals, i.e., mice and monkeys, the significance of these findings to humans is questionable. In embryo-fetal toxicity studies, maternal toxicity was noted in pregnant rats (including vaginal discharge, body weight loss) and rabbits (including mortality, body weight loss and abortion) at exposures that were 11 times and 2 times the letermovir exposures in HSCT patients, respectively. Developmental toxicity including common spontaneous malformations (additional lumbar/pelvic shift) and skeletal variations (additional rib), were observed at maternally toxic doses in both species.

In accordance with the International Council for Harmonization S1A Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals, carcinogenicity studies were not conducted since the proposed use of letermovir is less than 6 months.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Prevymis Product Monograph. In view of the intended use of Prevymis, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Prevymis Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Prevymis has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Based on the stability data submitted, the proposed shelf life of 30 months is acceptable when the tablets packed in aluminum foil blister and lidding are stored at temperature between 15°C to 30°C, and the vials are stored protected from light at temperature between 20°C to 25°C.

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.