AiCuris GmbH &Co KG, a clinical stage biopharmaceutical company developing drugs against severe infectious diseases, has reported positive results from its placebo-controlled and dose-ranging trial with Letermovir (AIC246). In addition to excellent efficacy Letermovir demonstrates superior tolerability and safety and thus defines a novel standard for the control of HCMV in transplant patients.

133 HCMV-seropositive allogeneic human blood precursor cell (HBPC) recipients were included in the trial. Given orally for 84 days, the two dosages of Letermovir, 120 mg and 240 mg once daily, meet both primary efficacy endpoints with high statistical significance vs. placebo. The efficacy endpoints are defined as incidence and time to onset of "HCMV prophylaxis failure". Under Letermovir treatment such failure, defined as development of systemic detectable HCMV replication (viral load above assay cut-off of 42 DNA copies/ml) or HCMV End-Organ Disease, is suppressed.

Prof. Richard Champlin, director of the worldwide largest Bone Marrow Transplantation Center in Houston, Texas comments: “CMV infections are a major cause of morbidity and mortality in patients undergoing haematopoietic transplantation. This study shows that Letermovir is a safe, effective treatment to prevent these infections. This is a major advance for the care of these immunocompromised patients.”

In the primary Full Analysis Population, the incidence of failure due to efficacy failure of prophylaxis or due to discontinuation of treatment for any other reason prior to Day 84, is significantly lower in the Letermovir 240 mg/day (29.4%; p=0.007) and 120 mg/day (32.3%; p=0.014) groups compared to placebo (63.6%). The incidence of HCMV prophylaxis failure amongst patients receiving treatment for at least seven days prior to HCMV replication was none for Letermovir 240 mg (p=0.004 vs. placebo) and only 2 patients for Letermovir 120 mg (p=0.109 vs. placebo). Similarly, the time to onset of prophylaxis failure among patients receiving 240 mg/day of Letermovir was significantly different (p=0.02) compared to patients receiving placebo.

Prof. Gerhard Ehninger, director of the Medical Clinic at the University Hospital in Dresden, Germany and one of the coordinating investigators of the trial adds, “The trial shows very convincing results in preventing HCMV reactivation. It becomes obvious that this drug with its novel mechanism of action offers clear benefits over existing therapies.”

Letermovir, whatever the daily dosage, is safe and well tolerated. In addition, the analysis of safety demonstrates that - in all Letermovir groups combined - the percentage of patients with at least one treatment emergent adverse event (TEAE) either considered related to the treatment by the investigator, or leading to discontinuation of treatment (17.3% and 25.5%, respectively) is lower than in the placebo group (33.3% and 57.6%, respectively).

“The safety data certainly look very good. There is no distressing signal for any significant toxicity in any of the Letermovir dose groups” says Prof. Per Ljungman, Head of Department at Karolinska University Hospital in Sweden and chairman of the Safety Monitoring Committee for this trial.

“On the basis of these encouraging efficacy and safety results with Letermovir in transplant recipients we are preparing phase III development” reports Dr Marie Paule Richard, CMO of AiCuris.

Prof. Helga Ruebsamen-Schaeff, CEO of AiCuris adds: “Our data indicate that a paradigm shift in bone marrow transplantation becomes feasible. Due to the excellent safety and efficacy of our drug it should now be possible to offer prophylaxis against HCMV to all patients undergoing this procedure at the time of transplantation or even earlier, rather than taking the risk of waiting for an HCMV infection to occur, before starting treatment.”

Letermovir (AIC246) is an innovative, highly active and specific inhibitor of HCMV. It stems from a novel chemical class (quinazolines) and addresses a novel target (the viral terminase). Based on this new mode of action, it retains full activity also against viruses which are resistant to marketed drugs (invariably inhibitors of the viral polymerase). It has received Orphan Drug Status in the US and EU and Fast Track Designation in the US.

Human cytomegalovirus (HCMV), a beta herpes virus, represents an important pathogen for immune compromised individuals. It is the most common virus pathogen in bone marrow and solid organ (kidney, heart, liver, lung and pancreas) transplant recipients. HCMV is the major cause of morbidity and mortality during the first six months after transplantation. HCMV disease is characterised by fever, leucopenia (very low white blood cells) and thrombocytopenia (very low platelet numbers) with or without specific organ dysfunction. Two main strategies to prevent HCMV disease have been adopted: anti-HCMV drug prophylaxis or pre-emptive treatment of transplant recipients who are at risk or have evidence of HCMV infection upon screening.

Besides transplant recipients, newborn children are highly threatened by HCMV infections. The infection can be acquired before, during or after birth and can lead to severe neurological damage or death. Because of the side effects of presently available drugs against HCMV, it is nearly impossible to treat these children. Neither can pregnant women with an active HCMV infection be treated.

Patients with AIDS might suffer from HCMV infection or disease, once HIV has caused a massive immune deficiency. In these patients, the virus might affect various organs and may e.g. lead to blindness or life threatening pneumonia. Thanks to HAART, severe AIDS cases with HCMV disease have become rare in the Western world. But in countries where access to anti-HIV therapy is not freely available such HCMV infections, in immune-compromised patients, are more common.

Increasing evidence is accumulating that even subclinical HCMV replication may be harmful, as HCMV is a virus, which is immune-suppressive on its own. For HIV-infected individuals several recent investigations showed that even when HIV is well-suppressed by HAART, the patients may not be able to control HCMV very well and may, as a consequence, suffer from a chronic and deleterious inflammation.

Similarly, HCMV also appears to pose a risk to patients under intensive care (e.g. after heart attack, suspected sepsis or burn). In this patient group, an active HCMV infection was found to be associated with increased time of hospitalisation and increased risk for death. Furthermore, in patients being treated for an auto-immune disease by the administration of immuno-suppressive agents, it has been observed that an opportunistic HCMV infection may occur while the patients are transiently immuno-compromised.