Pritelivir

Pritelivir (development codes AIC316 or BAY 57-1293) is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. It is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG. US FDA granted fast track designation for pritelivir in 2017 and breakthrough therapy designation 2020.

Medical use
Pritelivir is currently being developed for the treatment of immunocompromised patients with mucocutaneous HSV lesions that are resistant to acyclovir.

HSV in immunocompromised patients
Although HSV infection is very common in the general population, it rarely causes serious disease and is effectively contained by the immune system. In those with a weakened immune system such as transplant recipients, people receiving chemo- or radiotherapy, or HIV patients, an active HSV infection can cause disease in 35-68% of patients and may become severe or even life-threatening.

Standard of care treatments
HSV treatment revolves around the use of nucleoside analogues (NA) which act via the viral DNA polymerase, causing DNA chain termination and prevention of viral replication. First-line treatment is generally acyclovir or its prodrug valacyclovir. Resistance to acyclovir is more common in HSV patients with weakened or suppressed immune systems, affecting between 4 and 25% of cases.

Resistance to standard treatments
If HSV drug resistance is mediated by mutation(s) of the viral UL23 gene, which encodes the viral thymidine kinase (TK), then the pyrophosphate analogue foscarnet may be effective as a rescue treatment, since it does not require activation by TK. The use of foscarnet is commonly accompanied by restrictive toxicity, particularly nephrotoxicity. If the virus also acquires resistance to foscarnet, then there is currently no widely-approved and effective alternative treatment.

Completed phase II clinical trials in otherwise healthy patients with genital herpes

 * A Double-blind Randomized Placebo Controlled Dose-finding Trial to Investigate Different Doses of a New Antiviral Drug in Subjects With Genital HSV Type 2 Infection.
 * A Double-blind, Double Dummy, Randomized Crossover Trial to Compare the Effect of "AIC316 (Pritelivir)" 100 mg Once Daily Versus Valacyclovir 500 mg Once Daily on Genital HSV Shedding in HSV-2 Seropositive Adults.

Ongoing phase II / phase III clinical trials with pritelivir
A phase II / III multinational, comparator-controlled, clinical trial in immunocompromised patients with acyclovir-resistant mucocutaneous lesions is listed on ClinicalTrials.gov and EudraCT.

Mechanism of action
Pritelivir is a member of the helicase-primase inhibitors (HPI), a novel class of direct-acting antiviral drugs acting specifically against HSV-1 and HSV-2. As the name suggests, the drugs act through inhibition of the viral helicase primase complex, encoded by the UL5 (helicase), UL8 (scaffold protein) and UL52 (primase) genes, which is essential for HSV replication. The helicase primase complex is encoded separately from the viral DNA polymerase (encoded by the UL30 gene). Because HPIs i) do not target the viral DNA polymerase and ii) do not require activation by the viral thymidine kinase enzyme (encoded by the UL23 gene), mutations causing resistance to NAs are not protective against HPIs. Similarly, resistance to HPIs does not confer resistance to NAs.