Letermovir Treatment of Human Cytomegalovirus Infection Antiinfective Agent.

NIH Public Access Author Manuscript Drugs Future. Author manuscript; available in PMC 2013 October 25.

NIH-PA Author Manuscript

Published in final edited form as: Drugs Future. 2013 May ; 38(5): 291–298.

Letermovir Treatment of Human Cytomegalovirus Infection Antiinfective Agent Priya S. Verghese and University of Minnesota Medical School Department of Pediatrics, Division of Pediatric Nephrology, Amplatz Children’s Hospital, East Building, MB680, 2414 South 7th Street, Minneapolis, MN 55454, Phone: 612-626-2922, Fax: 612-626-2791 Mark R. Schleiss University of Minnesota Medical School Department of Pediatrics, Division of Pediatric Infectious Diseases, Center for Infectious Diseases and Microbiology Translational Research, 2001 6th Street SE, Minneapolis, MN 55455, Phone: 612-624-1112, Fax: 612-626-9924 Priya S. Verghese: [email protected]; Mark R. Schleiss: [email protected]


Summary Novel therapies are urgently needed for the management of cytomegalovirus (CMV) disease in high-risk patients. Currently licensed agents target the viral DNA polymerase, and although they are effective, they are fraught with toxicities to patients. Moreover, emergence of antiviral resistance is an increasing problem, particularly for patients on long-term suppressive therapy. A new agent, letermovir (AIC246), shows great promise for the management of CMV infection. Advantages include its good oral bioavailability, its lack of toxicity, and the apparent absence of drug-drug interactions. Letermovir has a novel mechanism of action, exerting its antiviral effect by interfering with the viral pUL56 gene product and in the process disrupting the viral terminase complex. This agent demonstrates substantial promise as an alternative to more toxic antivirals in patients at high risk for CMV disease, particularly in the transplantation setting.

Background


Infections with human cytomegalovirus (CMV) are generally asymptomatic in healthy hosts, but can cause severe disease in immune suppressed patients, including patients with advanced HIV disease, hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) patients as well as congenitally infected patients [1]. In patients with advanced AIDS, CMV is known to cause severe end-organ disease and reactivation of CMV is a co-factor in the acceleration of HIV infection [2–4]. The advent of modern immunosuppression has dramatically improved transplant graft survival but there has been a corresponding increase in infections like CMV[5, 6]. Without some form of CMV prevention, up to 75% of all patients undergoing SOT experience new infection or reactivation of latent CMV [7]. CMV disease can manifest post-transplant as fever, leukopenia, or mild to severe organ involvement with occasional mortality. Symptomatic disease also includes viremia, pneumonitis, enteritis, and retinitis, and CMV infections posttransplant increase the probability of an allograft recipient developing post-transplant lymphoproliferative disorder (PTLD) due to co-infection with Epstein Barr virus [8, 9]. In addition to symptomatic disease, CMV reactivation also has consequences for graft survival and organ function in SOT recipients [10–13]. CMV can also cause severe disability in the congenitally infected fetus, including sensorineural hearing loss that may progressively worsen after birth [14]. Thus, there is a compelling need for antiviral therapies that target CMV for use in several patient populations.

Verghese and Schleiss

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The development of nucleoside antivirals, particularly ganciclovir (GCV), has had a substantial impact on CMV infection and disease in high-risk populations [15–17]. Ganciclovir, and its oral prodrug, valganciclovir (Val-GCV), are utilized in virtually all patients at risk for CMV disease following SOT. One of two strategies are employed by most centers: either universal prophylaxis, the administration of GCV or Val-GCV to all at risk patients for 3–12 months; or preemptive therapy, where patients are monitored at regular intervals for early evidence of CMV replication (usually based on the appearance of CMV antigen or nucleic acids in the bloodstream) and treatment is initiated before symptom or end-organ disease can develop [18, 19]. Antiviral prophylaxis or preemptive therapy are effective in preventing CMV disease in modest-risk CMV-seropositive SOT recipients, and it appears to be associated with improved graft survival [20] and antiviral prophylaxis is emerging as the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients, particularly CMV-seronegative recipients of allografts from CMV-seropositive donors [21]. However, there are substantial shortcomings to both approaches. Break-through infections can occur, emergence of antiviral resistance is a serious concern, and late onset CMV disease has been observed following discontinuation of prophylaxis [22]. Thus, while GCV and Val-GCV have been highly effective in preventing and treating CMV disease in SOT patients [23, 24] and somewhat effective in ameliorating the severity of CMV disease in the setting of congenital infection [25], new therapies are need, particularly to deal with the problem of GCV-resistance [23, 26, 27]. The only other approved anti-CMV drugs are foscarnet (FOS) and cidofovir (CDF) that, like GCV, target the viral DNA polymerase to exert their antiviral effect. However, these drugs are highly toxic, in particularly carrying a substantial risk of nephrotoxicity [28–31]. Antiviral resistance is also observed with CDF and FOS. Since GCV, CDF, and FOS share the same molecular target, the viral DNA polymerase pUL54, drug-resistant strains of CMV carrying UL54 mutations have been found that confer resistance to all three drugs, with reported cross-resistance for some mutations [32]. There is therefore incentive to identify newer antiCMV agents with different mechanisms of action to avoid shared resistance with GCV and with safer side effect profiles.


To fill the void in available agents to avoid the toxicity of anti-CMV antivirals, or to treat GCV-resistant CMV disease, several experimental agents have recently been developed and evaluated in clinical trials [33]. These drugs include maribavir, CMX001 and letermovir (AIC246). These new agents are summarized in Table 1. Two Phase 3 studies of maribavir, a competitive inhibitor of the pUL97 protein, as CMV prophylaxis, have been performed; one in allogeneic HSCT recipients and the other in liver transplant recipients. In both studies, although maribavir was safe, its efficacy for CMV prevention was sub-optimal [34], [35] and the study in HSCT patients was halted prematurely due to its failure to prevent CMV viremia [34]. Although some experts consider the failure of the HSCT maribavir trial to be dose related [36], the future of this drug is uncertain particularly since resistance to maribavir has already been reported [37]. CMX001 is a novel, broad-spectrum lipid antiviral conjugate that produces high intracellular levels of the active antiviral agent cidofovir diphosphate. A randomized, double-blind, placebo-controlled, dose-escalating study in healthy volunteers performed to evaluate the safety and pharmacokinetic parameters of CMX001 after single and multiple doses demonstrated good oral bioavailability and the drug was well tolerated in healthy volunteers [38]. In a Phase 2 trial of CMX001 in stem cell transplant recipients, a reduction in new or progressive CMV infection was observed in those receiving higher doses of CMX001 (≥200mg weekly) but there was reported doselimiting diarrhea in this group [39]. In spite of the challenges and limitations observed with novel anti-CMV agents, clinical trials of these agents remain a major priority. The focus of this monograph is to review the mechanism of action and clinical pharmacology of another novel CMV antiviral, letermovir, and discuss its potential for impacting the therapy of CMV disease. Drugs Future. Author manuscript; available in PMC 2013 October 25.


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Preclinical Pharmacology Development of Letermovir


As noted, antivirals against CMV have in the past chiefly targeted the viral DNA polymerase. Antiviral resistance to GCV is based upon emergence of mutations in the viral protein kinase pUL97 leading to a lack of synthesis of GCV-triphosphate, the active form of the drug [40],[41]. UL97 mutations have also been linked to maribavir resistance, suggesting that the pUL97 kinase, in addition to phosphorylating GCV to its active form, is itself a potential antiviral target [42],[43]. The discovery of letermovir came out of attempts to study compounds targeting a different viral function: the viral terminase complex, which consists of the viral gene products pUL89 andpUL56[33]. In addition to the terminase subunits pUL56 and pUL89, at least five additional HCMV proteins, namely, pUL51, pUL52, pUL77, pUL93, and pUL104, contribute to this process [44, 45]. Antivirals targeting this complex are particularly intriguing, since the terminase complex is a uniquely viral function, and so target-related toxicities of a terminase–inhibitor would be unlikely given the lack of a human counterpart. Members of the class of terminase inhibitors include BDCRB, GW275175X, and BAY 38-4766 [33, 46, 47]. Letermovir is the most recently characterized member of this terminase inhibitor family. Structurally, it is member of a novel class of lowmolecular-weight compounds, 3,4 dihydro-quinazolines. It was discovered during attempts at identifying a terminase-inhibitor by screening a compound library in a high-throughput manner with structure-activity relationship studies and pharmacological analyses [48]. The molecular formula of letermovir is C29H28F4N4O4and its molecular weight is 572.550633 [g/mol]. The chemical structure is demonstrated in Figure 1. Its pre-clinical profile indicated that it was highly selective in its antiviral activity for CMV, demonstrating little activity against other human or rodent herpesviruses, and minimal activity against other human pathogenic viruses, hepadnavirus, adenovirus, retroviruses, orthomyxoviruses, and flaviviruses [49]. The selectivity index (SI), which is the CC50 (amount of drug required to kill 50% of uninfected cells) divided by the EC50 (amount of drug needed to cause 50% inhibition of viral replication), is greater than 15,000 for letermovir, therefore demonstrating not only excellent overall antiviral activity but also a remarkable lack of cellular toxicity [50]. Mechanism of action


Letermovir has shown potent in vitro and in vivo activity against CMV [48, 49] by acting late in the CMV replication cycle. Its mechanism of action is illustrated in Figure 2. Longbranched, head-to-tail concatemers are formed during CMV DNA replication. Site-specific cleavage by the CMV terminase complex converts concatemeric progeny DNA to unitlength genomes and the packaging of those genomes into preformed procapsids ensues. The small terminase subunit, pUL89, is required for DNA duplex nicking, and pUL56, the large subunit, mediates the sequence-specific binding to concatemeric viral DNA, in the process providing energy for DNA translocation via its ATPase activity. The pUL51 protein is a third member of the terminase complex that has been recently characterized in detail. It colocalizes with pUL89 and pUL56, and is required for cleavage of concatermeric DNA, although its mechanism of action is incompletely elucidated [45]. In addition to these viral gene products, a number of other viral genes are involved in the process of cleavage and assembly [33]. Letermovir interacts with the viral pUL56 subunit [51], [52] and therefore blocks viral replication without inhibiting the synthesis of progeny CMV DNA or viral proteins. This mechanism is distinct from that of the DNA polymerase inhibitors. Notably, there is a lack of cross-resistance to other identified terminase inhibitors (BDCRB, GW275175X, and BAY 38-4766) which suggests that letermovir has a unique putative binding domain on the pUL56 subunit [52]. Specific mutations in the UL56 coding sequence

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have been identified that confer resistance to AIC246, confirming that pUL56 is a molecular target of this agent [52].


Pharmacokinetics and Metabolism The pharmacokinetic properties of AIC246 have been monitored in nine Phase I trials so far [39, 40]. After a single oral dose, absorption is reported to occur rapidly with median Tmax of 1.5 hours, and a mean terminal elimination half-life of 10 hours [39]. Letermovir has been administered to over 230 healthy subjects, either as a single dose or repeated doses for up to 14 days. In an open-label, proof-of-concept trial (Phase IIa), 27 transplanted patients with CMV viremia were enrolled and treated pre-emptively with daily doses of 80 mg letermovir for 14 days [48]. The reduction in viral CMV DNA load in kidney-transplanted patients was similar when compared with the local standard treatment at the investigational site, and no patient was noted to develop CMV disease while on therapy. In addition, the efficacy of 1 × 80 mg and 2 × 40 mg per day was comparable, indicating that once-daily dosing is feasible. It is noteworthy that in this trial, letermovir was used to successfully treat a lung transplant patient who developed multi-resistant CMV pneumonitis on Val-GCV prophylaxis (described in greater detail below) [53].

Safety NIH-PA Author Manuscript

No tolerability or safety issues related to letermovir treatment occurred during the treatment period in either phase I or phase IIa studies. In all trials, letermovir was generally well tolerated as no dose-dependent adverse events occurred and no effects on safety laboratory parameters, vital signs or electrocardiogram (ECG) parameters have been reported [50].

Clinical Studies Current status of clinical trials


As noted above, phase 1 clinical trials have demonstrated that letermovir has a favorable pharmacokinetic profile allowing once daily dosing with good tolerability in more than 200 healthy volunteers [50]. In addition, the phase IIa data from an open-label study including 27 kidney and kidney/pancreas recipients who were treated for 14 days with preemptive letermovirhad comparable efficacy to Val-GCV. During the Phase II study, a cystic fibrosis patient s/p bilateral lung transplant developed CMV pneumonitis despite Val-GCV prophylaxis; which progressed to retinitis and colitis despite therapy with CMX001, ValGCV, leflunomide, CDV and an artemisin derivative. Letermovir was initiated in this patient at 120mg and 240mg every other day for 49 days. CMV viremia resolved on Day 28 with resolution of colitis, pneumonitis and retinitis. The patient had no adverse effects to the letermovir and reportedly remained CMV-relapse free for 4 months following the cessation of therapy [53]. A Phase IIb randomized placebo controlled double-blinded dose escalation trial of letermovir on CMV prevention in HSCT recipients has recently been completed (clinicaltrials.gov identifier:NCT01063829). One hundred and thirty-two HSCT recipients met entry criteria and were CMV seropositive within a year of the transplant, had no detectable CMV replication within 5 days of starting study drug, and were transplanted within 40 days of randomization. The study participants were randomized to 60mg, 120mg, 240 mg vs. placebo once daily with 33 recipients in each group. Participants underwent weekly testing for CMV PCR and/or antigenemia for the 84 days they were on study drug and 7 days after cessation of the drug. Failure of prophylaxis defined as the development of detectable CMV replication or CMV-related end organ damage leading to discontinuation of study drug, occurred in 21%, 19%, 6% and 36% in the 60mg daily, 120mg daily, 240mg



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daily of letermovir and placebo groups respectively. On the inclusion of study participants that did not complete the entire course of study drug for reasons other than true prophylaxis failure (example death, adverse event, non-compliance or withdrawal of consent); the incidence of failure of prophylaxis was 48%, 32%, 29% and 64% in the 60 mg daily, 120 mg daily, 240 mg daily dose of letermovir and placebo groups respectively [Table 2]. The drug appeared to be safe in this reported studies. Treatment emergent adverse events considered related to the treatment or leading to discontinuation of treatment was lower in those receiving letermovir (17.3% and 25.5%) than placebo (33.3% and 57.6%, respectively) although details are not available (http://www.ukmi.nhs.uk/applications/ndo/ record_view_open.asp?newDrugID=5485).

Drug Interactions In the open-label, proof-of-concept study of letermovir [54], it was reported that coadministration of this agent with immunosuppressive drugs in patients did not result in a need for major adjustments of the co-administered immunosuppressants. In the patient with multi-drug resistant CMV, tacrolimus levels did not require any adjustments while the patient was on letermovir therapy [53]. To date, no drug-drug interactions have been reported for letermovir.


Sources Letermoviris being developed by AiCuris GmbH & Co KG, a privately held company located in Wuppertal, Germany. AiCuris recently announced a partnership with Merck to enter into an exclusive worldwide license agreement for future investigational studies of letermovir. The FDA recently granted “orphan drug” status to letermovir.

Acknowledgments Acknowledgements/Disclosures Grant support from NIH HD044864 is acknowledged.

References


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FIGURE 1.

The 2-dimensional structure of letermovir. From: http://pubchem.ncbi.nlm.nih.gov/ summary/summary.cgi?cid=45138674



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FIGURE 2.

Simplified schematic representation of mechanism of action of letermovir compared to other CMV antivirals. For more detailed overview of CMV replication see [57]. Panel A, early events in CMV DNA replication. Following infection of cell, viral nucleocapsid traffics to nucleus (1), followed by entry of linear viral DNA into nuclear compartment via nuclear pore (2). Viral genomic DNA then circularizes (3), followed by initiating of viral DNA replication via a rolling circle mechanism (4). This is the stage in CMV replication where DNA polymerase (pUL54) inhibitors (namely ganciclovir, cidofovir, and foscarnet) exert their antiviral effect. Long-branched, head-to-tail concatemers are formed during this phase of CMV DNA replication (5). Panel B, mode of action of letermovir. After rolling circle replication of multiple concatemers of genomic DNA (1), a collection of viral proteins known as the CMV terminase complex converts concatemeric progeny DNA to unit-length genomes (2). The major components of the terminase complex are pUL89 and pUL56 (the



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molecular target of letermovir). CMV proteins pUL51, pUL52, pUL77, pUL93, and pUL104 also contribute to the terminase complex. Subsequently, the packaging of these unit length genomes into preformed procapsids ensues (3) prior to egress of the mature nucleocapsid through the nuclear membrane (4), the next step in virion assembly. Inhibition of cleavage of concatermeric DNA into unit length genomes prevents completion of viral replication. Since letermovir works at a later stage of CMV replication than DNA polymerase inhibitors, other CMV proteins are made in infected cells in the context of exposure to this antiviral. This in turn might theoretically translate to development of antiviral immune responses to these proteins in patients treated with letermovir, compared to ganciclovir, although this is speculative and has not been evaluated in clinical studies.

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TABLE 1


Comparison of new anti-CMV drugs in clinical trials. AIC246 (letermovir), CMX001 (lipid conjugate of cidofovir), and maribavir (a member of the benzimidazole family of compounds). Comparative dose, drug mechanism, and toxicities are compared.


AIC246

CMX001

Maribavir

Dose

80 mg daily oral

200 mg orally once weekly OR 100 mg twice weekly

400 daily or 400 bid*

Compound information

Novel class of lowmolecular-weight compounds, 3,4 dihydroquinazolines

Lipid antiviral conjugate comprised of a lipid (1-0-hexadecyl-oxypropyl) covalently linked to the acyclic nucleotide analogue cidofovir

Benzimidazole nucleoside

Mechanisms of action

Terminase inhibitor: blocks viral replication without inhibiting the synthesis of progeny CMV DNA or viral proteins

Remains intact in plasma and deliver drug directly to the target cell resulting in enhanced cellular uptake and high intracellular levels of cidofovir (CDV) diphosphate which competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA by viral DNA polymerase. This disrupts further chain elongation [55]

Inhibition of viral encapsidation and nuclear egress of viral particles from infected cells

Toxicities

None reported

Mild side effects include abdominal pain or discomfort, and aphthous stomatitis [38]

Taste disturbance, Skin rash [56]

Viral gene targets

Viral pUL56 subunit

Viral DNA polymerase

Viral pUL97 kinase

*

Maribavir 100 mg bid did not have sufficient anti-CMV activity in liver transplant patients. 400 mg daily and 400 mg bid have been shown to be safe but anti-CMV activity is not clear.

NIH-PA Author Manuscript Drugs Future. Author manuscript; available in PMC 2013 October 25.


Page 13

TABLE 2


Incidence of CMV prophylaxis failure in Phase IIb randomized placebo controlled double-blinded dose escalation trial of letermovir on CMV prevention in HSCT recipients Letermovir N (%) patients

60 mg daily N=33

120 mg daily N=31

240 mg daily N=34

Placebo daily N=33

Patients who developed detectable CMV disease and/or replication

21%

19%

6%

36%

Discontinuation of trial medications before Day 84*

27%

13%

24%

27%

Total that failed prophylaxis

48%

32%

30%

63%

*

Reasons were varied and included death, withdrawal of consent, adverse event and non-compliance

NIH-PA Author Manuscript NIH-PA Author Manuscript Drugs Future. Author manuscript; available in PMC 2013 October 25.

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