Helicase-primase inhibitor pritelivir, also known as AIC316, reduced the rates of genital herpes simplex virus (HSV-2) in a dose-dependent manner in a proof-of-concept trial involving otherwise healthy men and women infected by HSV-2.

The study was published in the January 16 issue of the New England Journal of Medicine.

Anna Wald, MD, MPH, from the University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington, and colleagues randomly assigned 156 HSV-2-positive patients either to 1 of 4 different doses of pritelivir or to placebo for 28 days. The doses were 5, 25, or 75 mg daily or 400 mg a week.

Study participants were asked to take daily swabs from the genital area that they then gave to researchers once a week for HSV-2 testing by polymerase chain reaction assay. Participants also were asked to maintain a diary of genital signs and symptoms and if they had a recurrence during the study period, to return to the clinic for examination within 24 hours.

Through the polymerase chain reaction testing, the researchers detected HSV-2 shedding on 18.2% of days among patients receiving 5 mg pritelivir daily, on 9.3% of days among patients taking 25 mg daily, on 2.1% of days among patients taking 75 mg daily, and on 5.3% of days among patients taking 400 mg a week. That compares with detection of HSV-2 shedding on 16.6% of days among patients taking placebo.

The researchers also observed that the percentage of days with genital lesions came to 1.2% for 2 pritelivir groups (75 mg: relative risk [RR], 0.13 [95% confidence interval (CI), 0.02 - 0.70]; 400 mg: RR, 0.13 [95% CI, 0.03 - 0.52]) compared with 9.0% for the placebo group.

The researchers observed no adverse event patterns or laboratory abnormalities during the study, although 3 of 9 participants who discontinued the study did so because of various events, including moderate headache, suspected lupus erythematosus, or anxiety. Patients taking 400 mg a week experienced more nausea than patients taking the other pritelivir doses. The researchers observed no evidence of drug resistance.

The trial took place between April and December 2010 at 7 clinical sites in the United States. AiCuris, the German pharmaceutical company that makes pritelivir, funded the study, and AiCuris employees participated in the study and the writing of the report.

Study participants were 67% women and 68% to 74% white, depending on treatment group, and had a median age of 41 years. Of the 156 original participants, 147 (94%) completed the study. Researchers calculated the mean adherence to study medication, according to pill count, at 99%. Participants submitted 4180 swabs, of which 435 came in positive for HSV-2.

On Hold

The US Food and Drug Administration placed clinical development of pritelivir on hold in May 2013 (during a phase 2 study), the researchers write, "because of unexplained dermal and hematologic findings in a toxicology study of monkeys treated with daily doses ranging from 75 mg per kilogram of body weight to 1000 mg per kilogram (these doses were 70 to more than 900 times as high as a dose of 75 mg in humans). The reason for the findings in monkeys is currently under investigation; such findings were not observed in the current trial."

In a telephone interview with Medscape Medical News, Jonathan Zenilman, MD, professor of medicine and chief of the Division of Infectious Diseases at Johns Hopkins Bayview Medical Center, Baltimore, Maryland, and a member of the Infectious Diseases Society of America's public health committee, said, "It would be very disappointing if it turns out" that pritelivir may infer toxicity.

He said the new study is important for 2 primary reasons: pritelivir is in a new class of herpes drugs, and this research was done by the premier herpes therapeutics group.

"This is exciting because this is actually a different mechanism," he said, explaining that older herpes drugs are DNA polymerase inhibitors with different pharmacokinetic and toxicity profiles. Some patients who are resistant to them often have major systemic problems. When viruses replicate, their DNA helix has to uncoil to replicate with fidelity, and "this drug actually prevents the DNA from even uncoiling."

In addition, Dr. Zenilman explained, the outcome measures used in the study are laboratory measures that are not necessarily clinical. "That is important because most herpes patients are asymptomatic. It is important from the point that the [US Food and Drug Administration] is accepting this as an outcome measure, but also for future studies. It actually makes clinical trials more efficient. This is like a pivotal trial on that number of patients, and the reason they could do that is because the prevalence of shedding is actually much higher than the number of clinical episodes."

Potential Combination Treatment

Pritelivir also offers potential as a combination treatment for patients who need to take cyclovir, Dr. Zenilman said.

In an accompanying editorial, Richard J. Whitley, MD, and Mark Pritchard, MD, from the University of Alabama at Birmingham, also see that potential: "For those providing care to patients with life-threatening HSV infections, the potential for combination therapy may now be possible, and studies to assess this opportunity are under way."

This study was funded and sponsored by AiCuris. Dr. Wald has reported receiving consulting fees from Amgen and travel support from Vical. One coauthor has reported owning stock in Immune Design and being a coinventor on several HSV-2 vaccine patents, 5 coauthors are AiCuris employees, 1 coauthor has reported contributing to relevant patents, 1 coauthor has reported receiving consulting fees from Immune Design; 1 coauthor has reported receiving travel support from AiCuris, and 1 coauthor has reported receiving travel support from Vical. Several coauthors have reported receiving grant support through their institutions from up to 5 companies. The other authors have disclosed no relevant financial relationships. Dr. Whitley has reported receiving fees for consulting or board service from N&N Scientific and Gilead Sciences, for CME review from George Washington University, lecturing at Washington University, and royalties from Henry Stewart Talks, as well as serving as associate editor of the Journal of Infectious Diseases.

N Engl J Med. Published online January 15, 2014. Article abstract, Editorial extract