AiCuris GmbH & Co. KG gained FDA fast-track designation – and valuable mindshare – for its lead drug AIC246 (letermovir), a viral terminase inhibitor that combats human cytomegalovirus (CMV) infection. It is currently undergoing a Phase IIb trial in bone marrow transplant recipients, who are receiving the drug prophylactically, in order to prevent the dormant virus from re-emerging and causing active infection.
The FDA's fast-track designation "shows that the agency is really very interested in this drug," AiCuris CEO Helga Rübsamen-Schaeff told BioWorld Today. It also serves to emphasize that the available options are inadequate.
Efficacy data from the 132-patient study are expected before the end of the year, so the Wuppertal, Germany-based firm does not expect to have an end-of-Phase-II meeting with FDA officials until sometime next year. However, the company has already seen encouraging safety signals, including the absence of drug-drug interactions when AIC246 is administered along with immunosuppressive drugs.
"The safety data look very promising," Rübsamen-Schaeff said. "This is remarkable because [the trial is] in bone marrow stem cell recipients, who are a very vulnerable population."
CMV, a member of the herpes family of DNA viruses, is endemic, but usually dormant in the human population. Although several drugs are already approved for combating the virus, most target the viral DNA polymerase, giving rise to concerns about the emergence of cross-resistance. AIC246 targets the UL56 subunit of the viral terminase complex, which is responsible for viral DNA processing and packaging.
The existing polymerase inhibitors are, moreover, toxic to the immune system and are generally unavailable orally. These drugs, which include ganciclovir, valganciclovir (an orally available prodrug of the same molecule), valacyclovir (an oral version of acyclovir), cidofovir and foscarnet, are therefore only administered in response to viral re-emergence.
AiCuris, which gained ownership of AIC246 when it was spun out of Bayer HealthCare (a subsidiary of Leverkusen, Germany-based Bayer AG) in 2006, aims to develop the drug as a safer prophylactic therapy.
Hematopoietic stem cell transplant recipients who have a latent CMV infection have a high probability of developing viremia, which carries a high mortality risk.
"It's a very significant problem in all recipients who are positive [for the virus]," Rübsamen-Schaeff said.
The company aims to secure a partner for AIC246 before embarking on a Phase III program. "We are at present discussing [a deal] with several potential partners," Rübsamen-Schaeff said.
The drug, which has already completed a Phase IIa trial in kidney transplant recipients, has potential application in several patient populations.
Rübsamen-Schaeff said the Phase III program is likely to include patients undergoing liver, lung or kidney transplantation, as well those receiving bone marrow transplants. "It's a minimum of three trials," she said.
The compound has further potential in preventing or treating congenital infection, which is a significant cause of childhood deafness, vision loss and mental retardation. CMV also is considered a likely cause of inflammation in HIV-infected patients, whose HIV levels are adequately controlled by HAART therapy.
Several alternative approaches to treating or preventing CMV infection are – or soon will be – under clinical investigation. London-based Cell Medica Ltd. is sponsoring a Phase III trial of an immunotherapy based on the delivery of T-cell memory cells that selectively target HCMV in bone marrow transplant patients.
4-Antibody AG, of Basel, Switzerland, aims to begin clinical trials this year of its lead antibody, 4Ab-028, which targets the CMV envelope protein gB.
Several vaccine development programs are under way as well. Earlier this year Astellas Pharma Inc., of Tokyo, licensed a DNA-based CMV vaccine from San Diego-based Vical Inc., which is being developed for both hematopoietic stem cell transplant and solid organ transplant recipients. A Phase III trial in the first indication is expected to get under way next year. Basel, Switzerland-based Novartis AG previously in-licensed a CMV vaccine program from AlphaVax Inc., of Research Triangle Park, N.C.
However, the prospects of eliminating CMV infection anytime soon are slim. "It will not be trivial," Rübsamen-Schaeff noted. "I don't see a vaccine in the near future."
In the meantime, the company also is preparing to meet with FDA officials to discuss plans for its non-nucleosidic herpes simplex virus drug, AIC316, which exhibited a dose-dependent effect on genital herpes infections in a recent Phase II trial. It too is likely to enter a Phase III trial next year.