bay-57-1293 and Herpes-Genitalis

Herpes simplex virus (HSV) types 1 and 2 can cause infections with clinical manifestations ranging from benign and generally self-limiting blisters or sores as seen in labial and genital herpes through to severe and in rare cases even life-threatening infections. At present, approved treatments for herpes simplex virus are almost all nucleoside analogs. Novel antiviral approaches include therapeutic vaccines, with the most advanced having successfully completed Phase 2 clinical development. Moreover, several small molecules approaches are being developed for the treatment of genital or labial HSV infections. Of particular interest are two novel compounds (amenamevir and pritelivir) belonging to the new class of helicase-primase inhibitors with promising Phase 2 data.

Topics: Acyclovir; Antiviral Agents; Clinical Trials, Phase II as Topic; DNA Helicases; DNA Primase; Drug Resistance, Viral; Herpes Genitalis; Herpes Simplex; Herpes Simplex Virus Vaccines; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Oxadiazoles; Pyridines; Sulfonamides; Thiazoles; Viral Proteins

Pritelivir is a novel helicase-primase inhibitor in clinical development for treatment of herpes simplex virus type 2 (HSV-2) infections. In preclinical work, resistance-mediating mutations were identified in the HSV-2 genome at 3 loci in the UL5 gene and 1 locus in UL52.. To evaluate whether daily pritelivir treatment results in emergence of resistance-mediating mutations, we analyzed HSV-2 strains detected in genital swab specimens from trial participants who were randomly assigned to receive different dosages of pritelivir. We sequenced resistance regions from 87 participants' samples, the UL5 gene in 73 samples from 44 participants, and the UL52 gene in 71 samples from 43 participants.. We found no evidence that pritelivir induced known resistance-mediating mutations or for amino acid variation at other loci. In one participant's HSV-2 isolate, we found a previously unidentified mutation close to the putative resistance-mediating region in UL5 and subsequently determined in vitro susceptibility to pritelivir. We characterized mutations from 32 cultivated HSV-2 isolates previously found to be susceptible to pritelivir in vitro and identified several novel mutations that most likely reflect preexisting variation in circulating HSV-2.. This study demonstrates evidence of retained susceptibility of HSV-2 to pritelivir in immunocompetent persons following daily therapy for up to 28 days.

Topics: Antiviral Agents; Drug Resistance, Viral; Female; Herpes Genitalis; Herpesvirus 2, Human; Humans; Male; Mutation; Pyridines; Sequence Analysis, DNA; Sulfonamides; Thiazoles; Viral Proteins

Current therapy of herpes infections relies on nucleoside analogues. Pritelivir is a well-tolerated novel herpes simplex virus (HSV) helicase-primase inhibitor that reduced genital shedding and lesions.. To compare the efficacy of pritelivir with valacyclovir for suppression of genital HSV-2 infection.. A phase 2, randomized, double-blind, crossover clinical trial at clinical research centers in 4 US cities (October 2012-July 2013) compared daily oral doses of 100 mg of pritelivir with 500 mg of valacyclovir. The planned sample size was 98 adults, allowing for detection of a 50% reduction in viral shedding between the study treatments. Healthy adults with 4 to 9 annual genital HSV-2 recurrences were eligible. 45 participants were randomized to receive pritelivir [corrected] and 46 to receive valacyclovir first when the US Food and Drug Administration placed the trial on clinical hold based on findings in a concurrent nonclinical toxicity study, and the sponsor terminated the study.. Participants took the first drug for 28 days followed by 28 days of washout before taking the second drug for 28 days. Throughout treatment, the participants collected genital swabs 4 times daily for testing by HSV polymerase chain reaction assays.. The primary end point was within-participant genital HSV shedding while receiving pritelivir compared with valacyclovir. Secondary end points included the quantity of HSV in positive swabs and the frequency of genital lesions and shedding episodes.. Of the 91 randomized participants (median age, 48 years; 57 women [63%]), 56 had completed both treatment periods at the time of the study's termination. In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7453) during valacyclovir treatment (relative risk [RR], 0.42 [corrected]; 95% CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, -0.1; 95% CI, -0.6 to 0.5; P = .83). Genital lesions were present on 1.9% of days in the pritelivir group vs 3.9% in the valacyclovir group (RR, 0.40; 95% CI, 0.17-0.96; P = .04). The frequency of shedding episodes did not differ by group, with 1.3 per person-month for pritelivir and 1.6 per person-month for valacyclovir (RR, 0.80; 95% CI, 0.52 to 1.22; P = .29). Treatment-emergent adverse events occurred in 62.3% of participants in the pritelivir group and 69.2% of participants in the valacyclovir group.. Among adults with frequently recurring genital HSV-2, the use of pritelivir compared with valacyclovir resulted in a lower percentage of swabs with HSV detection over 28 days. Further research is needed to assess longer-term efficacy and safety.. clinicaltrials.gov Identifier: NCT01658826.

Topics: Acyclovir; Adult; Aged; Antiviral Agents; Cross-Over Studies; Double-Blind Method; Female; Herpes Genitalis; Herpesvirus 2, Human; Humans; Male; Middle Aged; Pyridines; Recurrence; Sulfonamides; Thiazoles; Valacyclovir; Valine; Virus Shedding; Young Adult

Pritelivir, an inhibitor of the viral helicase-primase complex, exhibits antiviral activity in vitro and in animal models of herpes simplex virus (HSV) infection. We tested the efficacy and safety of pritelivir in otherwise healthy persons with genital HSV-2 infection.. We randomly assigned 156 HSV-2-positive persons with a history of genital herpes to receive one of four doses of oral pritelivir (5, 25, or 75 mg daily, or 400 mg weekly) or placebo for 28 days. Participants obtained daily swabs from the genital area for HSV-2 testing, which was performed with a polymerase-chain-reaction assay. Participants also maintained a diary of genital signs and symptoms. The primary end point was the rate of genital HSV shedding.. HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups.. Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dose-dependent manner in otherwise healthy men and women with genital herpes. (Funded by AiCuris; ClinicalTrials.gov number, NCT01047540.).

Topics: Administration, Oral; Adult; Aged; Antiviral Agents; DNA, Viral; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral; Female; Herpes Genitalis; Herpesvirus 2, Human; Humans; Male; Middle Aged; Polymerase Chain Reaction; Pyridines; Sulfonamides; Thiazoles; Viral Load; Virus Shedding

Topics: Acyclovir; Antiviral Agents; Herpes Genitalis; Herpesvirus 2, Human; Humans; Immunocompromised Host; Sulfonamides; Thiazoles

Patients with Herpes Simplex Virus-2 (HSV-2) infection face a significantly higher risk of contracting HIV-1. This is thought to be due to herpetic lesions serving as entry points for HIV-1 and tissue-resident CD4+ T cell counts increasing during HSV-2 lesional events. We have created a stochastic and spatial mathematical model describing the dynamics of HSV-2 infection and immune response in the genital mucosa. Using our model, we first study the dynamics of a developing HSV-2 lesion. We then use our model to quantify the risk of infection with HIV-1 following sexual exposure in HSV-2 positive women. Untreated, we find that HSV-2 infected women are up to 8.6 times more likely to acquire HIV-1 than healthy patients. However, when including the effects of the HSV-2 antiviral drug, pritelivir, the risk of HIV-1 infection is predicted to decrease by up to 35%, depending on drug dosage. We estimate the relative importance of decreased tissue damage versus decreased CD4+ cell presence in determining the effectiveness of pritelivir in reducing HIV-1 infection. Our results suggest that clinical trials should be performed to evaluate the effectiveness of pritelivir or similar agents in preventing HIV-1 infection in HSV-2 positive women.

Topics: Antiviral Agents; CD4-Positive T-Lymphocytes; Computational Biology; Computer Simulation; Female; Genitalia, Female; Herpes Genitalis; Herpesvirus 2, Human; HIV Infections; HIV-1; Humans; Immunity, Mucosal; Models, Biological; Pyridines; Risk Factors; Sexual Behavior; Stochastic Processes; Sulfonamides; Thiazoles

Topics: Antiviral Agents; Female; Herpes Genitalis; Herpesvirus 2, Human; Humans; Male; Pyridines; Sulfonamides; Thiazoles; Virus Shedding

The efficacy of BAY 57-1293, a novel non-nucleosidic inhibitor of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus and pseudorabies virus, was studied in the guinea pig model of genital herpes in comparison with the licensed drug valaciclovir (Valtrex). Early therapy with BAY 57-1293 almost completely suppressed the symptoms of acute HSV-2 infection, and reduced virus shedding and viral load in the sacral dorsal root ganglia by up to three orders of magnitude, resulting in decreased latency and a greatly diminished frequency of subsequent recurrent episodes. In contrast, valaciclovir showed only moderate effects in this set of experiments. When treatment was initiated late during the course of disease after symptoms were apparent, that is, a setting closer to most clinical situations, the efficacy of therapy with BAY 57-1293 was even more pronounced. Compared with valaciclovir, BAY 57-1293 halved the time necessary for complete healing. Moreover, the onset of action was fast, so that only very few animals developed new lesions after treatment commenced. Finally, in a study addressing the treatment of recurrent disease in animals whose primary infection had remained untreated BAY 57-1293 was efficient in suppressing the episodes. In summary, superior potency and efficacy of BAY 57-1293 over standard treatment with valaciclovir was demonstrated in relevant animal models of human genital herpes disease in terms of abrogating an HSV infection, reducing latency and the frequency of subsequent recurrences. Furthermore, BAY 57-1293 shortens the time to healing even if initiation of therapy is delayed.

Topics: Animals; Antiviral Agents; Disease Models, Animal; DNA Helicases; DNA Primase; DNA, Viral; Enzyme Inhibitors; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Humans; Polymerase Chain Reaction; Pyridines; Sulfonamides; Thiazoles