U.S. FDA Accepts for Priority Review the Supplemental New Drug Application for Merck’s PREVYMIS™ for Prophylaxis of Cytomegalovirus Disease in Kidney Transplant Recipients at High Risk

Rhea-AI Summary

Merck (NYSE: MRK) announced that the FDA accepted two supplemental new drug applications (sNDA) for PREVYMIS™ (letermovir). The first application is for CMV prophylaxis in kidney transplant recipients at high risk, with a PDUFA target date of June 5, 2023. The second extends prophylaxis from 100 to 200 days for patients receiving allogeneic HSCT, target date Sept. 7, 2023. PREVYMIS demonstrated non-inferior efficacy and a superior safety profile to the current standard of care, valganciclovir, in clinical trials. This acceptance could present a significant advance in treatment options for high-risk transplant patients.

Positive

• FDA granted priority review for PREVYMIS sNDA in kidney transplant recipients.
• PREVYMIS showed non-inferior efficacy and a better safety profile over valganciclovir.
• Clinical trial data supports extended prophylaxis for a broader patient base.

Negative

• None.

FDA also accepts a separate supplemental application to extend prophylaxis with PREVYMIS to 200 days in certain HSCT recipients

RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the U.S. Food and Drug Administration (FDA) has accepted for review two supplemental new drug applications (sNDA) for PREVYMIS™ (letermovir). The FDA granted priority review for the sNDA for PREVYMIS for prophylaxis of cytomegalovirus (CMV) disease in adult kidney transplant recipients at high risk (D+/R-); the Prescription Drug User Fee Act (PDUFA), or target action date, is June 5, 2023. The FDA grants priority review to medicines and vaccines that, if approved, would provide a significant improvement in the safety or effectiveness of the treatment or prevention of a serious condition. A second sNDA to extend use of PREVYMIS from 100 days to 200 days in adults receiving an allogeneic hematopoietic stem cell transplant (HSCT) who are at risk for late CMV infection and disease was also accepted for review, with a PDUFA date of Sept. 7, 2023.

“Certain high-risk individuals who develop CMV infection following receipt of a kidney transplant are at increased risk for transplant failure and death. PREVYMIS has the potential to be an important new option with a favorable safety profile for patients at risk for CMV infection following a kidney transplant,” said Dr. Nicholas Kartsonis, senior vice president, vaccines and infectious diseases, Global Clinical Development, Merck Research Laboratories. “We look forward to the FDA’s review of our filings for PREVYMIS.”

PREVYMIS is a first-in-class antiviral agent that was approved by the U.S. FDA in 2017 and is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

Data supporting the sNDA for CMV prophylaxis in kidney transplant recipients

The sNDA for use of PREVYMIS for CMV prophylaxis in kidney transplant recipients is supported by a Phase 3, randomized, double-blind clinical trial (NCT03443869) that demonstrated non-inferior efficacy and a more favorable safety profile for PREVYMIS compared to valganciclovir, the current standard of care for CMV prophylaxis in kidney transplant recipients. Data from the trial were presented during a late-breaking oral session at the IDWeek Annual Meeting in October 2022.

Key safety results

In the study, PREVYMIS had a more favorable safety profile compared to valganciclovir, with fewer drug-related adverse events (AEs) and study drug discontinuations due to adverse events reported in the PREVYMIS group compared to the valganciclovir group. The incidence of leukopenia (decrease in leukocytes, or white blood cells) and neutropenia (decrease in neutrophils, the most common type of white blood cell) was lower with PREVYMIS than with valganciclovir:

• The treatment difference in leukopenia/neutropenia was 38% lower in the PREVYMIS group versus the valganciclovir group and was statistically significant (95% CI, -45.1, -30.3; p value = <0.0001);
• Neutropenia measured during treatment through week 28 post-transplant (absolute neutrophil count <1000 cells/µL) was reported in 4.1% (n=12) of the PREVYMIS group versus 19.5% (n=58) of the valganciclovir group (95% CI, -20.7, -10.5);
• Leukopenia and neutropenia leading to discontinuation of study drug during the 28-week treatment phase was reported in 1.0% (n=3) in the PREVYMIS group and 5.4% (n=16) in the valganciclovir group, and 1.4% (n=4) in the PREVYMIS group and 1.7% (n=5) in the valganciclovir group, respectively.

Additional safety information from the trial:

• Drug-related AEs were reported in 19.9% (n=58) of PREVYMIS participants and 35.0% (n=104) of valganciclovir participants through week 28 post kidney transplant (95% CI, −22.2, −8.0). Serious drug-related AEs were reported in 1.4% (n=4) of PREVYMIS participants and 5.1% (n=15) of valganciclovir participants (95% CI, −7.0, −0.9);
• Discontinuations due to an AE: 4.1% (n=12) in the PREVYMIS group and 13.5% (n=40) in the valganciclovir group (95% CI −14.1, −4.9);
• Discontinuation due to a serious AE: 2.1% (n=6) of PREVYMIS participants versus 4.7% (n=14) of valganciclovir participants (95% CI −5.9, 0.3);
• Discontinuation due to a drug-related AE: 2.7% (n=8) of PREVYMIS participants versus 8.8% (n=26) of valganciclovir participants (95% CI −10.1, −2.4);
• Discontinuation due to serious drug-related AE: 0.7% (n=2) of PREVYMIS participants versus 2.4% (n=7) of valganciclovir participants (95% CI −4.2, 0.4);
• Two participants (0.7%) in the PREVYMIS group and one participant in the valganciclovir group (0.3%) died (95% CI, −1.3, 2.2).

Data supporting the sNDA for 200 days of prophylaxis in HSCT patients

The sNDA for 200 days of prophylaxis with PREVYMIS is supported by a Phase 3, randomized, double-blind, placebo-controlled trial (NCT03930615) that evaluated the safety and efficacy of extending prophylaxis with PREVYMIS from 100 to 200 days, compared to placebo, in CMV-seropositive recipients [R+] at high risk for clinically significant CMV infection following an HSCT. This trial met its primary endpoint and prophylaxis with PREVYMIS extended to 200 days was superior to placebo in reducing the rate of clinically significant CMV infection from Week 14 through Week 28 post-HSCT in allogeneic R+ HSCT recipients. PREVYMIS had an adverse event profile similar to placebo and was well-tolerated. These data will be presented on Saturday, Feb. 18, at the 2023 Tandem Meetings / Transplantation & Cellular Therapy Meetings of ASTCT™ (American Society for Transplantation and Cellular Therapy) and CIBMTR^® (Center for International Blood & Marrow Transplant Research).

About PREVYMIS (letermovir)

PREVYMIS is the only drug approved in the United States for prophylaxis of CMV infection and disease in adults who are CMV-seropositive and have received an allogeneic HSCT. PREVYMIS is also approved in more than 60 countries outside of the United States, including EU member states, Canada, Japan and China. PREVYMIS is a first-in-class non-nucleoside CMV inhibitor (3,4 dihydro-quinazolines) and inhibits viral replication by specifically targeting the viral terminase complex. Cross resistance is not likely with drugs outside of this class. PREVYMIS is fully active against viral populations with substitutions conferring resistance to CMV DNA polymerase inhibitors. These DNA polymerase inhibitors are fully active against viral populations with substitutions conferring resistance to PREVYMIS. PREVYMIS has no activity against other viruses.

Selected Safety Information about PREVYMIS (letermovir)

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids. Increased pimozide concentrations may lead to QT prolongation and torsades de pointes. Increased ergot alkaloids concentrations may lead to ergotism. PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.

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.

The rate of adverse events in the first 100 days following HSCT occurring in at least 10% of transplant recipients treated with PREVYMIS and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).

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.

If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.

Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full Prescribing Information prior to and during treatment for potential drug interactions.

Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection.

PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.

The safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.

For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

About CMV

CMV is a common virus that infects people of all ages. Many adults in the United States are CMV-seropositive, meaning they have CMV antibodies in their blood, indicating a previous exposure to or primary infection with CMV. People with normal immune systems rarely develop CMV symptoms after initial infection, with the virus typically remaining inactive or latent in the body for life. A weakened immune system may give the virus a chance to reactivate, potentially leading to symptomatic disease or a secondary infection due to other pathogens. When a transplant recipient who is CMV-seronegative receives an organ from a donor who is CMV seropositive, the transplant recipient can get CMV from the donated organ. CMV disease can lead to end-organ damage, including gastrointestinal tract disease, pneumonia or retinitis. Transplant recipients who develop CMV infection post-transplant are at increased risk for transplant failure and death. CMV prophylaxis with certain existing antivirals has been associated with drug-specific effects, including myelosuppression and renal toxicity, in HSCT recipients.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA

This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of the global outbreak of novel coronavirus disease (COVID-19); the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2021 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for PREVYMIS at https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_pi.pdf and Patient Information/Medication Guide for PREVYMIS at https://www.merck.com/product/usa/pi_circulars/p/prevymis/prevymis_ppi.pdf.

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FAQ

What is the significance of the FDA's acceptance of Merck's sNDA for PREVYMIS?

The FDA's acceptance of the sNDA for PREVYMIS indicates that Merck's application for extending the use of the drug is under serious consideration, which could impact treatment protocols for transplant patients.

When is the PDUFA date for the PREVYMIS application for kidney transplant recipients?

The PDUFA date for the PREVYMIS application for kidney transplant recipients is June 5, 2023.

What does the sNDA for PREVYMIS entail?

The sNDA for PREVYMIS involves expanding its prophylactic use for cytomegalovirus (CMV) disease in high-risk kidney transplant patients and extending prophylaxis duration for HSCT patients.

What are the key benefits of PREVYMIS compared to current treatments?

PREVYMIS has shown a more favorable safety profile and lower incidence of adverse events compared to valganciclovir in clinical trials.

What is the second PDUFA date associated with Merck's PREVYMIS?

The second PDUFA date for the application to extend prophylaxis to 200 days for HSCT recipients is September 7, 2023.