Viral Infections
Letermovir (AIC246) – A Novel Drug Under Development for Prevention and Treatment of Cytomegalovirus Infections Acting via a Novel Mechanism of Action
Holger Zimmermann,1 Peter Lischka2 and Helga Rübsamen-Schaeff3 1. Chief Scientific Officer; 2. Senior Scientist; 3. Chief Executive Officer, AiCuris GmbH & Co KG
Abstract
Cytomegalovirus (CMV) remains an important pathogen for immunocompromised individuals, including transplant recipients, AIDS patients and newborns. It also increases morbidity and mortality in patients with temporal or partial immune suppression such as patients in intensive care units, highly active antiretroviral therapy (HAART)-treated HIV patients or patients with autoimmune disease. To date, all drugs licensed for the treatment of CMV infection and diseas e target the viral DNA polymerase. Although effective, there are several disadvantages associated with the use of these drugs, including toxicity and the emergence of drug resistance; hence, safe and improved antivirals with novel molecular targets are urgently needed. Letermovir (AIC246) belongs to a novel class of anti-CMV agents that exhibits outstanding antiviral activity and acts via a mechanism of action that is distinct from all currently approved drugs. In all clinical trials performed so far, AIC246 has been generally well tolerated in healthy subjects as well as in CMV-infected transplant patients. Efficacy was shown in a proof-of-concept trial in pre-emptively treated solid-organ transplant patients and a patient with multidrug-resistant CMV disease involving several organs. Results from a Phase IIb dose-finding trial for prophylactic use in human blood precursor cell transplanted patients are expected in early 2012.
Keywords AIC246, Letermovir, cytomegalovirus, antiviral therapy
Disclosure: Holger Zimmermann, Peter Lischka and Helga Rübsamen-Schaeff are employees of AiCuris. No writing assistance was utilised in the production of this manuscript. Received: 21 July 2011 Accepted: 8 August 2011 Citation: European Infectious Disease, 2011;5(2):112–4 Correspondence: Holger Zimmermann, AiCuris GmbH & Co KG, Friedrich-Ebert-Str. 475, 42117 Wuppertal, Germany. E:
holger.zimmermann@aicuris.com
Support: The publication of this article was funded by AiCuris GmbH & Co KG.
The human cytomegalovirus (CMV) is a member of the herpes virus family and is widely spread in the human population with seroprevalence rates varying from 40 up to almost 100 %, depending on socioeconomic status and geographic location. After primary infection, the virus remains in the latent state in its human host for a life-time and is activated in all instances of immune incompetence or immune suppression.1,2
Accordingly, CMV is the most common viral pathogen in solid organ transplant recipients (i.e., kidney, heart, liver, lung and pancreas) as well as in bone marrow, cord blood and human precursor blood cell transplant recipients. CMV infections observed in these patients are either a result of reactivation of latent virus in a CMV-seropositive recipient (R+) or of a primary infection being transmitted from a seropositive donor (D+) to a seronegative recipient.3,4
CMV infection is a major cause of morbidity and mortality in particular during the first six months after transplantation. Furthermore, CMV is the major viral cause of birth defects and developmental disorders after birth in the developed world. Congenital CMV infections can have devastating consequences for the foetus and it is estimated that approximately 0.2–2.2 % of life births in the US are born congenitally
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infected. Remarkably, only 10–15 % of infected newborns have clinical symptoms at birth, including central nervous system (CNS) abnormalities in the form of deafness, vision loss, microcephaly and mental retardation. The prognosis of those children who are symptomatic at birth is very poor and about 10 % of the affected infants die as a consequence of their CMV infection. However, also in 7–15 % of those children who are infected at birth and are asymptomatic, late sequelae (progressive hearing loss, learning or behavioural difficulties) may occur months or even years later.5,6 The impact of the consequences of congenital CMV infections on the social system has been estimated at US$1.8 billion per year.7
Moreover, in countries where treatment standards for HIV are low and HIV-infected patients develop AIDS, CMV is a significant pathogen in this patient population leading to severe disease and death.
However, CMV is also an immunopathogen in its own right. Recently, it has been recognised that CMV replication might be deleterious even in the absence of disease. Given this, additional patient groups where a (subclinical) CMV replication may add to morbidity and in some cases mortality are cancer patients treated with highly effective next-generation cytostatics, intensive care unit (ICU) patients and
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