Prevymis (letermovir), a treatment for preventing cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant patients, is bringing in another paradigm shift as it has entered the '200-day extension criteria.'

This drug's influence is expected to grow as the National Health Insurance (NHI) coverage period has been extended from the previous 100 days post-transplant to 200 days.

DailyPharm met with Professor Dong-Gun Lee of Seoul St. Mary's Hospital's Division of Infectious Diseases (President of the Korean Society of Infectious Diseases) to discuss the significance of Prevymis's reimbursement and future challenges.

The launch of Prevymis has brought a paradigm shift in infection management

CMV is a type of herpesvirus that lies dormant in the human body. Although it's common enough that 95% of Korean adults are seropositive for its antibodies, it is one of the most fatal infections for patients with weakened immunity due to hematopoietic stem cell transplantation or other factors.

Notably, CMV is reactivated in about two-thirds of patients within the first three to four months post-transplant. This can lead to serious complications such as pneumonia, gastroenteritis, retinitis, myelitis, and myelosuppression, and in some cases, can result in death.

Prevymis was approved by the Ministry of Food and Drug Safety (MFDS) in 2018 and approved for reimbursement in Korea in September of the same year. It is regarded as leading a paradigm shift from a preemptive therapy, defined as administering antiviral drugs to prevent infection, to a preventive therapy using Prevymis.

Professor Lee explained, "Typically, in 5 out of 10 allogeneic hematopoietic stem cell transplant patients, CMV is reactivated, and they endure lengthy anti-cancer treatments of up to 9 months and multiple hospitalizations before transplantation." He added, "Among existing antivirals, ganciclovir is an intravenous injection, requiring re-hospitalization for administration. Even with the oral valganciclovir, severe side effects like leukopenia often made it difficult to avoid hospitalization."

In this context, Professor Lee explained, Prevymis, which is available in both injectable and oral formulations and has a low toxicity burden, made it possible to continue preventive treatment without hospitalizing the patient.

It is particularly praised for its significant role in improving patient survival rates and treatment success rates by reducing the CMV reactivation rate to less than one-third of what it was, thereby significantly delaying the occurrence of CMV disease and the associated risk of death.

According to Professor Lee, when Prevymis was administered preventively, the reactivation rate within 100 days was lowered to about 5-6% in a U.S. clinical trial, and it was confirmed to be around 12-13% in data from Seoul St. Mary's Hospital.

Professor Lee stated, "If acute graft-versus-host disease (GVHD) occurs within approximately 100 days post-transplant, the patient's immune function is compromised, not only leading to CMV reactivation but also increasing the risk of other infections." He added, "If CMV is prevented during this period with Prevymis, the occurrence of CMV infection and related complications can be reduced."

Extended Prevymis Administration Shows Clear Efficacy, Prevents CMV Reactivation

There were also limitations to the 100-day prevention regimen with Prevymis. While the CMV reactivation rate decreased from the previous 50% to approximately 11-12% when Prevymis was administered for up to 100 days, the reactivation rate rose again once the drug was discontinued.

Data from Seoul St. Mary's Hospital showed that approximately one-third of patients experienced CMV reactivation between 100 and 200 days after completing the 100-day prevention regimen.

This means that since immunosuppression persists for up to six months post-transplant, and the risk of other viral or fungal infections remains high, patients can be exposed to various infection risks if there is a gap in preventive medication.

Professor Lee emphasized, "Extending the administration period to 200 days lowers the reactivation rate that occurs after 100 days to about 11%." He added, "This means that depending on how long Prevymis is administered, the timing of CMV reactivation can be delayed accordingly."

Based on this, the criteria for Prevymis reimbursement were expanded from 100 days to 200 days, effective June 1. Reimbursement is limited to high-risk adult patients who are CMV seropositive after allogeneic hematopoietic stem cell transplantation.

Professor Lee stated, "High-risk groups include patients with GVHD or those who received high-intensity conditioning regimens, and these are the patients eligible for the 200-day extended administration." He added, "In fact, more than 7-8 out of 10 hematopoietic stem cell transplant patients at Seoul St. Mary's Hospital fall into the high-risk group, and most of them receive extended Prevymis administration for up to 200 days."

In a pivotal Phase 3 study, which served as the basis for Prevymis's expanded reimbursement, the patient group that continued the prevention regimen for up to 200 days showed a 16.1% lower incidence of CMV infection compared to the placebo group. It also demonstrated a safety profile comparable to that of the placebo group during long-term administration.

Professor Lee emphasized, "During the recovery period, when immunity is compromised, there is a high risk of co-infections with other infectious diseases (respiratory viruses, other bacteria or viruses, and fungal infections) in addition to CMV. Extending Prevymis administration to 200 days to prevent CMV reactivation until the immune system recovers can also contribute to reducing the possibility of co-infections."

Despite expanded reimbursement criteria, unmet needs remain

However, challenges still exist. According to the reimbursement criteria, extended administration beyond 200 days is not possible for patients who are not classified as high-risk. In clinical practice, the high-risk status is meticulously evaluated around the 100-day mark to decide whether to extend the administration.

The problem arises in cases where patients are not high-risk at 100 days and stop taking the drug, only to see their risk increase later due to GVHD or other factors.

Professor Lee pointed out that under the current criteria, Prevymis cannot be re-administered to the same patient once it has been stopped. This results in an unmet need, as patients who require ongoing treatment are unable to receive it.

He stated, "Although continued administration would be clinically beneficial, there are actual cases where we cannot use Prevymis due to concerns about reimbursement cuts," and added, "Ultimately, these patients are exposed to the risk of CMV reactivation when their immunity is suppressed."

Overseas, there are reports of re-administering Prevymis within 200 days after a temporary treatment with other drugs. However, Professor Lee advised that this is not easy in Korea due to concerns about reimbursement cuts, necessitating additional institutional improvements.

Finally, as President of the Korean Society of Infectious Diseases, Professor Lee emphasized the need for a change in the public perception of preemptive or preventive drug administration for infectious diseases, which is often viewed as drug misuse or abuse.

Professor Lee explained, "For patient groups with severely compromised immunity, such as transplant or cancer patients, treating the disease after it has occurred is too late and dangerous," and added, "Preventive treatment for diseases with a high risk of onset is a matter of life and death for patients."

Professor Lee added, "Perceiving this as drug misuse overlooks the characteristics of infectious diseases and the reality of high-risk patients. Given that a significant portion of antibiotic misuse is in non-medical areas like livestock farming, we need to adjust the perception that attributes the cause of antibiotic resistance solely to doctors' misuse."