DUBLIN – Aicuris Anti-infective Cures GmbH is banking a €105 million (US$122 million) milestone from Merck & Co. Inc. on the back of an FDA approval of letermovir for preventing cytomegalovirus (CMV) reactivation in seropositive adults undergoing allogeneic hematopoietic stem cell transplant (HSCT). There could be cause for a double celebration shortly, as the drug is also up for decision at the EMA's Committee for Human Medicinal Products (CHMP).

The CHMP was due to conclude its monthly meeting Thursday, but had yet to disclose its opinion as of press time.

The FDA approval marks the end of an 11-year development journey for Wuppertal, Germany-based Aicuris. Letermovir, which Merck, of Kenilworth, N.J., will market as Prevymis, was on the point of entering the clinic when Aicuris was formed in 2006 as a spinout of the anti-infectives arm of Leverkusen, Germany-based Bayer AG. Merck stepped in five years ago, after the drug had delivered phase II data, with a deal that included €110 million up front and up to €332.5 million more in milestones. Aicuris is in line to receive further milestones based on approvals in other territories and in additional indications, as well as royalties on product sales. (See BioWorld Today, Oct. 16, 2012.)

The drug faces no immediate competition in its first indication, and it addresses a serious complication of HSCT. Because of the heavy immune suppression used in transplant protocols, recipients who have a latent infection have a high risk of their infection becoming active, which can lead to organ damage, transplant failure and death. Current standard of care involves the administration of preemptive antiviral drug therapy once patients start to exhibit early signs of viral reactivation. Those are not ideal, however. Toxicity and insufficient efficacy are both problems.

"I think this will have a very big impact, because for the first time you can shift the treatment paradigm in hematopoietic stem cell transplant patients," Aicuris CEO Holger Zimmerman told BioWorld.

Letermovir has gained accelerated approval on the basis of a single placebo-controlled phase III trial. Those who received the drug (n=325) had a prophylaxis failure rate of 38 percent, whereas 61 percent of those on placebo (n=170) experienced CMV reactivation. It also demonstrated a survival benefit. The all-cause mortality rate for those on drug was 12 percent and 24 percent at weeks 24 and 48, respectively, post-transplant. For those on placebo, the mortality rate was 17 percent and 28 percent at weeks 24 and 48, respectively.

There may be scope for further improvement of letermovir's efficacy, based on lengthening the dosing period from 100 days post-transplant to 200 days. "The FDA has taken a very close look at the data," Zimmerman said. "There might be a benefit if the treatment is given for longer."

The drug's safety profile makes that feasible. "It's very well-tolerated. There's a chance to treat for longer without running into problems with toxicity," he said. In the phase III study, the most commonly observed adverse events – which occurred in at least 10 percent of patients and at a frequency at least 2 percent greater than placebo – were nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue and abdominal pain, according to the drug's FDA label.

Study discontinuation rates were similar across the two study arms – 17 percent for those on letermovir and 16 percent for those on placebo. Its acceptable tolerability profile is linked to its mechanism of action, which is highly specific for CMV. It acts by inhibiting the CMV terminase complex, which is involved in the virus' rolling circle DNA replication process.

"There is no human counterpart for this," Zimmerman said. "It is only active against the CMV virus."

Letermovir has orphan drug designation on each side of the Atlantic. In the U.S., about 11,000 HSCT procedures are performed every year, and between 50 and 80 percent of recipients are seropositive for CMV, Zimmerman said.

Merck has not yet disclosed its intentions regarding additional indications. The most obvious, Zimmerman said, is prevention of CMV activation in patients undergoing solid organ transplant. Although CMV prophylaxis options exist in that setting, letermovir's safety and efficacy profile suggest it could be effective here, too, Zimmerman said.

Aicuris has four other programs in the clinic. Pritelivir (AIC-316), a herpes simplex virus (HSV) helicase-primase inhibitor, is undergoing phase II trials, in topical and oral formulations, for treating labial HSV infection and acyclovir-resistant HSV infection in immunocompromised patients. AIC-649, an immunomodulatory therapy in phase I development for hepatitis B virus infection, comprises an inactivated parapoxvirus ovis particle, which directs a T-cell response against HBV-infected cells. AIC-499 is a beta-lactam antibiotic, which demonstrates potency against multidrug-resistant gram-negative bacteria when combined with a beta-lactamase inhibitor. AIC-284 is an engineered version of interleukin-2, which targets regulatory T cells and has potential in autoimmune disease. It, too, is in phase I.

The company now has the cash to look at potential in-licensing opportunities as well as to continuing to fund its pipeline and in-house R&D, Zimmerman said.

The approval of letermovir is the second for a German growth-stage biopharmaceutical firm this year. It follows the approval in psoriasis in July of Tremfya (guselkumab), an IL-23 inhibitor originally discovered by Martinsried, Germany-based Morphosys AG and subsequently licensed to Johnson & Johnson, of New Brunswick, N.J. It will probably take more than that to reignite Germany's moribund investors, but it is further evidence that German firms can deliver the goods. And it also vindicates the commitment of billionaire brothers Thomas and Andreas Strüngmann, who are among the few stalwarts of German biotech. They are the main shareholders in Aicuris – and their stake has just increased in value.