Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

Figures & data

Table 1 Properties of the terminase inhibitor letermovir (AIC246)

	Description	Reference
Molecule type	3,4-dihydro-quinazoline-4-yl-acetic acid derivative	Lischka et al^Citation38
Mechanism of action	Inhibits terminase complex subunit pUL56	Goldner et al^Citation44
Known resistance mutations	UL56: L241P and R369S	Goldner et al^Citation46 Goldner et al^Citation45
Cross-resistance with other antivirals	None identified	Goldner et al^Citation44
	Letermovir remains active against CMV strains resistant to the other anti-CMV drugs GCV remains active against letermovir-resistant CMV strains	Goldner et al^Citation44
Spectrum of activity	Letermovir is only active against human CMV. No activity has been seen against non-human CMV, other herpesviruses, or any other virus	Marschall et al^Citation43
Clinical studies	Phase IIa: 27 solid organ transplant recipients with active CMV viral replication Findings: doses of 40 mg twice per day or 80 mg daily for 14 days reduced CMV DNA compared with baseline levels	Stoelben et al^Citation40
	Phase II: 131 CMV seropositive HSCT recipients Findings: letermovir groups had lower rates of prophylaxis failure than placebo (60, 120, or 240 mg of letermovir). Virologic failure was significantly lower in 240 mg group compared with placebo (6% versus 36%)	Chemaly et al^Citation42
Potential use in severe CMV disease	In vitro studies support its potential use in high viral load infections.	Lischka et al^Citation38
	The successful treatment of a multidrug-resistant CMV infection in a lung transplant recipient was reported	Kaul et al^Citation41
Side effects	Uncommon; letermovir is generally well tolerated	Kropeit^Citation47
	Gastroenteritis, nasopharyngitis, dyspnea, and elevation in serum creatinine	Stoelben et al^Citation40
	No reported neutropenia or other major laboratory alterations	Chemaly et al^Citation42
Pharmacokinetic parameters	Median Tmax was 1.5 hours Mean terminal t1/2 of 10 hours With food, median Tmax 4 hours, and Cmax was reduced by 24%, but the area under the curve was unchanged	Kropeit^Citation47
Dosing	Once-daily dose of 120 mg or 240 mg would achieve desirable levels without compromising its tolerability profile	Kropeit^Citation47 Chemaly et al^Citation42
Drug interactions	No significant drug interactions (only moderate increases in the levels of midazolam, tacrolimus, and cyclosporine were observed among healthy volunteers)	McCormick^Citation48
Potential future applications for letermovir	CMV prophylaxis of solid organ and stem cell transplant recipients First-line or second-line in the treatment of CMV disease Treatment of severe, multidrug-resistant CMV disease

Abbreviations: CMV, cytomegalovirus; GCV, ganciclovir; HSCT, hematopoietic stem cell transplant; T_max, time to maximum serum concentration; C_max, peak serum concentration; t_1/2, terminal half-life.

Figure 1 Representation of the different anti-CMV antivirals currently in use as well as letermovir, benzimidazole structure (BDCRB and TCRB), and the sulfonamide BAY 38-4766.

Abbreviations: CMV, cytomegalovirus; TCRB, 2,5,6-trichloro-1-β-D-ribofuranosyl benzimidazole; BDCRB, 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole.

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GoldnerTHempelCRuebsamen-SchaeffHZimmermannHLischkaPGeno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposureAntimicrob Agents Chemother201458161061324189264

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GoldnerTZimmermannHLischkaPPhenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovirAntiviral Res2015116c485025637709

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MarschallMStammingerTUrbanAIn vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic virusesAntimicrob Agents Chemother20125621135113722106211

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StoelbenSArnsWRendersLPreemptive treatment of cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a studyTranspl Int2014271778624164420

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ChemalyRFUllmannAJStoelbenSLetermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantationN Engl J Med2014370191781178924806159

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KaulDRStoelbenSCoberEFirst report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246Am J Transplant20111151079108421521474

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KropeitDPhase I safety and PK data of the novel anti-HCMV terminase inhibitor AIC246Abstract 1994 presented at the 50th Interscience Conference of Antimicrobial Agents and ChemotherapyBoston, MA, USASeptember 12–15, 2010

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MccormickDAIC246 does not exhibit clinically significant drug-drug interactions when administered with immunosuppressive drugs in transplant recipientPaper presented at: 51th Interscience Conference of Antimicrobial Agents and ChemotherapyChicago, IL, USASeptember 17–20 2011

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