Viral Infections
Table 2: Clinical Effect of AIC246 Treatment in Patients Infected with Ganciclovir-resistant Viruses
Response to Antiviral Therapy Virus 123-00125
Amino Acid Mutations Ganciclovir, Foscarnet, AIC246 (UL54/UL97)
Cidofovir UL54: E756D, A809V, - Case report26
K513N, S655L, N685S, V759M, A885T, N898D UL97: L595W UL54: A987G
UL97: A594T, C603W
that plays a key role in cleavage and packaging of CMV progeny DNA into capsids. This mechanism of action is expected to offer an advantage over current therapies given its antiviral efficacy without the target-related toxicity seen for the marketed nucleosidic anti-CMV drugs, since mechanism-based side effects are unlikely due to the lack of a mammalian counterpart of the viral terminase enzyme. In addition, the different mode of action of AIC246 should provide new treatment options for patients infected with resistant virus strains for which no effective therapy is currently available.23
Phase I Data
During clinical development, the safety, tolerability and pharmacokinetic properties of AIC246 have been monitored in nine Phase I trials so far.
After single oral dosing, absorption occurs rapidly with median tmax of 1.5 hours and a mean terminal elimination half-life of 10 hours. To date, AIC246 has been administered to more than 230 healthy male and female subjects, either as single doses or repeated doses for up to 14 days. In all trials, AIC246 was generally well tolerated as no dose-dependent adverse events occurred and no effects on safety laboratory parameters, vital signs and electrocardiogram (ECG) parameters were detected.24
Phase II Data
In an open-label proof-of-concept trial 27 transplanted patients with positive CMV viraemia were enrolled and treated pre-emptively with daily doses of 80 mg AIC246 for 14 days. The reduction in viral CMV DNA titres in kidney-transplanted patients was similar compared with the local standard treatment of the investigational site and no patient developed CMV disease under therapy. Also, the efficacy of 1 x 80 mg and 2 x 40 mg
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5. Boppana SB, Fowler KB, Pass RF, et al., Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss, J Pediatr, 2005;146(6):817–23.
6. Grosse SD, Ross DS, Dollard SC, Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment, J Clin Virol, 2008;41(2):57–62.
7. Arvin AM, Fast P, Myers M, et al., Vaccine development to prevent cytomegalovirus disease: Report from the national vaccine advisory committee, Clin Infect Dis, 2004;39:233–9.
8. Hunt PW, Martin JN, Sinclair E, et al., Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy, J Infect Dis, 2011;203(10):1474–83.
9. Wiltshire H, Hirankarn S, Farrell C, et al., Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients, Clin Pharmacokinet, 2005;44:495–507.
10. Wiltshire H, Paya CV, Pescovitz MD, et al., Pharmacodynamics +
per day was comparable, indicating that once-daily dosing is feasible. Notably, in this trial, AIC246 was also used to successfully treat a patient harbouring a multi-resistant CMV strain for the marketed anti-CMV drugs GCV, CDV and FOS, confirming the resistance-breaking potential seen in the in vitro studies (see Table 2). Overall, AIC246 co-administration with immunosuppressive drugs in patients did not result in a need for major adjustments of the co-administered immunosuppressants. Moreover, no tolerability or safety issues related to AIC246 treatment occurred during AIC246 treatment.25
- + Emergency Use of AIC246
AIC246 was successfully used to treat a lung-transplanted patient with refractory multidrug resistant CMV disease involving three organs (lung, colon and eye) under an US Emergency Investigational New Drug (EIND) application (see Table 2). Resolution of viraemia was reached after 28 days on treatment. Clinical and radiological resolution of CMV pneumonitis, retinitis and colitis was achieved by 33 days of AIC246 therapy. Patient plasma quantitative CMV polymerase chain reaction (PCR) remained undetectable over a four-month follow-up period. No tolerability or safety issues related to AIC246 treatment occurred during the treatment period.26
Summary
AIC246 is derived from a novel chemical class and acts via a novel mechanism of action compared with drugs on the market and in development. This novel drug is highly active against the human CMV and is resistance breaking versus viruses resistant to all currently used compounds. Phase I trials demonstrated that AIC246 was generally well tolerated and showed a high and long-lasting exposure in human subjects, allowing once-daily dosing. Moreover, proof of concept for efficacy was shown in a Phase IIa trial in solid-organ-transplanted patients treated pre-emptively and in a patient infected with a multidrug-resistant virus suffering from multi-organ CMV disease. As such, AIC246 appears to be a promising new drug with resistance-breaking properties suitable for treatment and prevention of CMV infection and disease. A Phase IIb multicentre, randomised, double-blind, placebo-controlled dose escalation trial of AIC246 for prevention of CMV infection/reactivation in haematopoietic stem cell transplant recipients has enrolled all patients (
clinicaltrials.gov identifier: NCT01063829) and results should be available in early 2012. n
of oral ganciclovir and valganciclovir in solid organ transplant recipients, Transplantation, 2005;79:1477–83.
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16. Limaye AP, Corey L, Koelle DM, et al., Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants, Lancet, 2000;356:645–9.
17. Eckle T, Lang P, Prix L, et al., Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery, Bone Marrow Transplant, 2002;30:433–9.
18. Gilbert C, Boivin G, Human cytomegalovirus resistance to antiviral drugs, Antimicrob Agents Chemother, 2005;49:873–83.
19. Scott GM, Weinberg A, Rawlinson WD, Chou S, Multidrug resistance conferred by novel DNA polymerase mutations in human cytomegalovirus isolates, Antimicrob Agents Chemother, 2007;51:89–94.
20. Reefschlaeger J, Bender W, Hallenberger S, et al., Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38- 4766): in vitro and in vivo antiviral activity and mechanism of action, J Antimicrob Chemother, 2001;48(6):757–67.
21. Buerger I, Reefschlaeger J, Bender W, et al., A novel nonnucleoside inhibitor specifically targets cytomegalovirus DNA maturation via the UL89 and UL56 gene products, J Virol, 2001;75(19):9077–86.
22. Lischka P, Hewlett G, Wunberg T, et al., In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246, Antimicrob Agents Chemother, 2010;54(3):1290–7.
23. Goldner T, Hewlett G, Ettischer N, et al., The novel anti-cytomegalovirus compound AIC246 inhibits HCMV replication through a specific antiviral mechanism that involves the viral terminase, J Virol, 2011;(Epub ahead of print).
24. Kropeit D, McCormick D, VonRichter O, et al., Phase I safety and PK data of the novel anti-HCMV terminase inhibitor AIC246, Abstract 1994, Presented at: the 50th Interscience Conference Antimicrobial Agents Chemother (ICAAC), Boston, MA, 12–15 September 2010.
25. Zimmermann H, Stoelben S, Renders L, et al., A novel non-nucleoside compound with activity against human cytomegalovirus – overview of clinical trials and resistance breaking activity, Abstract V1256b, Presented at: the 49th Interscience Conference Antimicrobial Agents Chemother (ICAAC), San Francisco, CA, 12–15 September 2009.
26. Kaul DR, Stoelben S, Cober E, et al., First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246, Am J Transplant, 2011;11:1079–84.
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