New agent shortened HSV-2 shedding

Pritelivir, "the first in a new class of antiviral agents developed for the treatment of herpes simplex infections," suppressed viral shedding and lesion formation in a small proof-of-concept study funded by the drug’s manufacturer and reported online Jan. 15 in the New England Journal of Medicine.

The drug is the first in its class that inhibits HSV replication by targeting the HSV helicase–primase enzyme complex. Findings from this study showed that the investigational agent markedly reduced both the frequency of HSV shedding on the genital mucosa in otherwise healthy men and women and, when breakthrough shedding did occur, decreased the quantity of virus shed by more than 98%, said Dr. Anna Wald, professor in the division of allergy and infectious diseases at the University of Washington in Seattle, and her associates.

Pritelivir also significantly reduced the number of days when genital lesions were present. Because the study was not powered to assess the effect on symptomatic recurrences, this must be considered a preliminary finding to be explored in future studies, they added.

The investigators noted that the Food and Drug Administration placed a hold on the clinical development of pritelivir in May 2013 "because of unexplained dermal and hematologic findings in a toxicology study of monkeys treated with daily doses ranging from 75 mg per kg to 1,000 mg per kg." These doses were 70 to more than 900 times as high as a dose of 75 mg in humans. No such adverse events were observed in this trial.

Dr. Wald and her colleagues assessed the drug’s safety and efficacy in their double-blind, dose-finding study that involved 155 otherwise healthy men and women who had had HSV 2 infection for a median of 11 years and who had up to nine recurrences each year. The median age of the study subjects was 41 years. Most (67%) were women, and 75% were white.

These participants were treated and followed at seven medical centers in the United States. They provided daily swabs of genital skin and mucosa for HSV detection and kept diaries of genital signs and symptoms throughout the trial.

The patients were randomly assigned to five study groups: pritelivir at daily doses of 5 mg (33 subjects), 25 mg (32 subjects), or 75 mg (29 subjects); a weekly dose of 400 mg (31 subjects); or daily placebo (30 subjects). They were treated for 28 days.

The 75-mg dose was found to have the greatest effectiveness against HSV 2.

HSV shedding in the reference (placebo) group occurred on 16.6% of days. In comparison, HSV shedding occurred on 18.2% of days with 5-mg pritelivir; 9.3% of days with 25 mg; 2.1% of days with 75 mg; and 5.3% of days with 400 mg weekly, Dr. Wald and her associates reported (N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMoa1301150]).

The drug was similarly effective in men and women. For example, HSV shedding occurred on 3.2% of days in men taking 75-mg pritelivir, compared with 12.5% of days in men taking placebo. Similarly, HSV shedding occurred on 1.6% of days in women taking 75-mg pritelivir, compared with 18.3% of days in women taking placebo, they said.

When HSV shedding was detected, the median log-10 number of DNA copies was 5.1 with placebo, 4.5 with 5-mg pritelivir, 3.6 with 25-mg pritelivir, 2.4 with 75-mg pritelivir, and 3.6 with 400-mg pritelivir. Thus, at the 75-mg dose, pritelivir reduced the quantity of HSV DNA in breakthrough shedding by more than 98%.

The researchers also assessed the percentage of days on which study participants had genital lesions. The rate was 1.2% of days in the 75-mg group, compared with 9% with placebo, 12.5% with 5-mg pritelivir, 3.5% with 25-mg pritelivir, and 1.2% with 400-mg pritelivir.

"No pattern of adverse events or laboratory abnormalities emerged during the study," although the 1-month duration of treatment was short, Dr. Wald and her associates wrote. Three participants discontinued treatment because of adverse events: one patient reported moderate headache, nausea, chest pain, and dyspnea; the second was suspected to have systemic lupus erythematosus, which disqualified her from participating further; and the third withdrew because of mild anxiety.

Six other patients withdrew for other reasons or were lost to follow-up, one withdrew because she became pregnant, and another was noncompliant with the study protocol. One final patient developed pancreatitis 2 weeks after completing treatment, but this was considered to be unrelated to the drug because the patient had had prior episodes of alcohol-related pancreatitis and was believed to have resumed drinking when the study ended.

Although pritelivir markedly reduced the rate of viral shedding, some breakthrough shedding still occurred. "The question of whether further increases in the daily dose of pritelivir would completely abrogate viral shedding will have to be addressed in additional studies," they said.

Since pritelivir targets a different pathway than nucleoside analogues such as acyclovir, future studies also should investigate the effectiveness of combination therapy, the investigators added.

This study was funded by AiCuris. Dr. Wald reported ties to Agenus, Amgen, Genentech, Genocea, Gilead, and Vical. Her associates reported numerous relevant financial disclosures.

Pritelivir, "the first in a new class of antiviral agents developed for the treatment of herpes simplex infections," suppressed viral shedding and lesion formation in a small proof-of-concept study funded by the drug’s manufacturer and reported online Jan. 15 in the New England Journal of Medicine.

The drug is the first in its class that inhibits HSV replication by targeting the HSV helicase–primase enzyme complex. Findings from this study showed that the investigational agent markedly reduced both the frequency of HSV shedding on the genital mucosa in otherwise healthy men and women and, when breakthrough shedding did occur, decreased the quantity of virus shed by more than 98%, said Dr. Anna Wald, professor in the division of allergy and infectious diseases at the University of Washington in Seattle, and her associates.

Pritelivir also significantly reduced the number of days when genital lesions were present. Because the study was not powered to assess the effect on symptomatic recurrences, this must be considered a preliminary finding to be explored in future studies, they added.

The investigators noted that the Food and Drug Administration placed a hold on the clinical development of pritelivir in May 2013 "because of unexplained dermal and hematologic findings in a toxicology study of monkeys treated with daily doses ranging from 75 mg per kg to 1,000 mg per kg." These doses were 70 to more than 900 times as high as a dose of 75 mg in humans. No such adverse events were observed in this trial.

Dr. Wald and her colleagues assessed the drug’s safety and efficacy in their double-blind, dose-finding study that involved 155 otherwise healthy men and women who had had HSV 2 infection for a median of 11 years and who had up to nine recurrences each year. The median age of the study subjects was 41 years. Most (67%) were women, and 75% were white.

These participants were treated and followed at seven medical centers in the United States. They provided daily swabs of genital skin and mucosa for HSV detection and kept diaries of genital signs and symptoms throughout the trial.

The patients were randomly assigned to five study groups: pritelivir at daily doses of 5 mg (33 subjects), 25 mg (32 subjects), or 75 mg (29 subjects); a weekly dose of 400 mg (31 subjects); or daily placebo (30 subjects). They were treated for 28 days.

The 75-mg dose was found to have the greatest effectiveness against HSV 2.

HSV shedding in the reference (placebo) group occurred on 16.6% of days. In comparison, HSV shedding occurred on 18.2% of days with 5-mg pritelivir; 9.3% of days with 25 mg; 2.1% of days with 75 mg; and 5.3% of days with 400 mg weekly, Dr. Wald and her associates reported (N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMoa1301150]).

The drug was similarly effective in men and women. For example, HSV shedding occurred on 3.2% of days in men taking 75-mg pritelivir, compared with 12.5% of days in men taking placebo. Similarly, HSV shedding occurred on 1.6% of days in women taking 75-mg pritelivir, compared with 18.3% of days in women taking placebo, they said.

When HSV shedding was detected, the median log-10 number of DNA copies was 5.1 with placebo, 4.5 with 5-mg pritelivir, 3.6 with 25-mg pritelivir, 2.4 with 75-mg pritelivir, and 3.6 with 400-mg pritelivir. Thus, at the 75-mg dose, pritelivir reduced the quantity of HSV DNA in breakthrough shedding by more than 98%.

The researchers also assessed the percentage of days on which study participants had genital lesions. The rate was 1.2% of days in the 75-mg group, compared with 9% with placebo, 12.5% with 5-mg pritelivir, 3.5% with 25-mg pritelivir, and 1.2% with 400-mg pritelivir.

"No pattern of adverse events or laboratory abnormalities emerged during the study," although the 1-month duration of treatment was short, Dr. Wald and her associates wrote. Three participants discontinued treatment because of adverse events: one patient reported moderate headache, nausea, chest pain, and dyspnea; the second was suspected to have systemic lupus erythematosus, which disqualified her from participating further; and the third withdrew because of mild anxiety.

Six other patients withdrew for other reasons or were lost to follow-up, one withdrew because she became pregnant, and another was noncompliant with the study protocol. One final patient developed pancreatitis 2 weeks after completing treatment, but this was considered to be unrelated to the drug because the patient had had prior episodes of alcohol-related pancreatitis and was believed to have resumed drinking when the study ended.

Although pritelivir markedly reduced the rate of viral shedding, some breakthrough shedding still occurred. "The question of whether further increases in the daily dose of pritelivir would completely abrogate viral shedding will have to be addressed in additional studies," they said.

Since pritelivir targets a different pathway than nucleoside analogues such as acyclovir, future studies also should investigate the effectiveness of combination therapy, the investigators added.

This study was funded by AiCuris. Dr. Wald reported ties to Agenus, Amgen, Genentech, Genocea, Gilead, and Vical. Her associates reported numerous relevant financial disclosures.

Pritelivir, "the first in a new class of antiviral agents developed for the treatment of herpes simplex infections," suppressed viral shedding and lesion formation in a small proof-of-concept study funded by the drug’s manufacturer and reported online Jan. 15 in the New England Journal of Medicine.

The drug is the first in its class that inhibits HSV replication by targeting the HSV helicase–primase enzyme complex. Findings from this study showed that the investigational agent markedly reduced both the frequency of HSV shedding on the genital mucosa in otherwise healthy men and women and, when breakthrough shedding did occur, decreased the quantity of virus shed by more than 98%, said Dr. Anna Wald, professor in the division of allergy and infectious diseases at the University of Washington in Seattle, and her associates.

Pritelivir also significantly reduced the number of days when genital lesions were present. Because the study was not powered to assess the effect on symptomatic recurrences, this must be considered a preliminary finding to be explored in future studies, they added.

The investigators noted that the Food and Drug Administration placed a hold on the clinical development of pritelivir in May 2013 "because of unexplained dermal and hematologic findings in a toxicology study of monkeys treated with daily doses ranging from 75 mg per kg to 1,000 mg per kg." These doses were 70 to more than 900 times as high as a dose of 75 mg in humans. No such adverse events were observed in this trial.

Dr. Wald and her colleagues assessed the drug’s safety and efficacy in their double-blind, dose-finding study that involved 155 otherwise healthy men and women who had had HSV 2 infection for a median of 11 years and who had up to nine recurrences each year. The median age of the study subjects was 41 years. Most (67%) were women, and 75% were white.

These participants were treated and followed at seven medical centers in the United States. They provided daily swabs of genital skin and mucosa for HSV detection and kept diaries of genital signs and symptoms throughout the trial.

The patients were randomly assigned to five study groups: pritelivir at daily doses of 5 mg (33 subjects), 25 mg (32 subjects), or 75 mg (29 subjects); a weekly dose of 400 mg (31 subjects); or daily placebo (30 subjects). They were treated for 28 days.

The 75-mg dose was found to have the greatest effectiveness against HSV 2.

HSV shedding in the reference (placebo) group occurred on 16.6% of days. In comparison, HSV shedding occurred on 18.2% of days with 5-mg pritelivir; 9.3% of days with 25 mg; 2.1% of days with 75 mg; and 5.3% of days with 400 mg weekly, Dr. Wald and her associates reported (N. Engl. J. Med. 2014 Jan. 15 [doi:10.1056/NEJMoa1301150]).

The drug was similarly effective in men and women. For example, HSV shedding occurred on 3.2% of days in men taking 75-mg pritelivir, compared with 12.5% of days in men taking placebo. Similarly, HSV shedding occurred on 1.6% of days in women taking 75-mg pritelivir, compared with 18.3% of days in women taking placebo, they said.

When HSV shedding was detected, the median log-10 number of DNA copies was 5.1 with placebo, 4.5 with 5-mg pritelivir, 3.6 with 25-mg pritelivir, 2.4 with 75-mg pritelivir, and 3.6 with 400-mg pritelivir. Thus, at the 75-mg dose, pritelivir reduced the quantity of HSV DNA in breakthrough shedding by more than 98%.

The researchers also assessed the percentage of days on which study participants had genital lesions. The rate was 1.2% of days in the 75-mg group, compared with 9% with placebo, 12.5% with 5-mg pritelivir, 3.5% with 25-mg pritelivir, and 1.2% with 400-mg pritelivir.

"No pattern of adverse events or laboratory abnormalities emerged during the study," although the 1-month duration of treatment was short, Dr. Wald and her associates wrote. Three participants discontinued treatment because of adverse events: one patient reported moderate headache, nausea, chest pain, and dyspnea; the second was suspected to have systemic lupus erythematosus, which disqualified her from participating further; and the third withdrew because of mild anxiety.

Six other patients withdrew for other reasons or were lost to follow-up, one withdrew because she became pregnant, and another was noncompliant with the study protocol. One final patient developed pancreatitis 2 weeks after completing treatment, but this was considered to be unrelated to the drug because the patient had had prior episodes of alcohol-related pancreatitis and was believed to have resumed drinking when the study ended.

Although pritelivir markedly reduced the rate of viral shedding, some breakthrough shedding still occurred. "The question of whether further increases in the daily dose of pritelivir would completely abrogate viral shedding will have to be addressed in additional studies," they said.

Since pritelivir targets a different pathway than nucleoside analogues such as acyclovir, future studies also should investigate the effectiveness of combination therapy, the investigators added.

This study was funded by AiCuris. Dr. Wald reported ties to Agenus, Amgen, Genentech, Genocea, Gilead, and Vical. Her associates reported numerous relevant financial disclosures.