pritelivir (AIC316) / AiCuris - LARVOL DELTA

How We Diagnose and Manage Refractory and Resistant Herpes Simplex Virus Mucocutaneous Infection After Hematopoietic Cell Transplantation. (PubMed, Clin Microbiol Infect) - "The proposed R/R HSV mucocutaneous infection diagnostic and treatment algorithm guides the appropriate management of these difficult-to-treat infections, potentially improving patient outcomes."

Journal • Review • Bone Marrow Transplantation • Herpes Simplex • Human Immunodeficiency Virus • Infectious Disease • Transplantation

Combined use of pritelivir with acyclovir or foscarnet suppresses evolution of HSV-1 drug resistance. (PubMed, Virus Evol) - "PFA + PTV dual treatment induced PFA resistance mutations in the DP, but PTV resistance mutations were not acquired, even after 15 passages. Our data suggest that combining the helicase-primase inhibitor PTV with a DP inhibitor may be an effective strategy to prevent drug resistance evolution in HSV-1."

Journal • Herpes Simplex • Infectious Disease

PRIOH-1: Trial on Efficacy and Safety of Pritelivir Tablets for Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects (clinicaltrials.gov) - P3 | N=153 | Recruiting | Sponsor: AiCuris Anti-infective Cures AG | Trial completion date: Apr 2025 ➔ Nov 2025 | Trial primary completion date: Jan 2025 ➔ Jul 2025

Trial completion date • Trial primary completion date • Herpes Simplex • Infectious Disease

Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy. (PubMed, J Control Release) - "Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue...Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy against two highly prevalent sexually transmitted infections (STIs)."

Journal • Herpes Simplex • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • CXCL8 • IFNG • IL10 • IL12A • IL17A • IL18 • IL1B • IL6 • TNFA

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Pritelivir and Its Metabolites. (PubMed, Clin Pharmacol Drug Dev) - "A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment."

Journal • PK/PD data • Hepatology • Renal Disease

Helicase-primase inhibitors for the treatment of herpes simplex virus infections - patent evaluation of WO2023/225162 from gilead sciences inc. (PubMed, Expert Opin Ther Pat) - "With amenamevir already approved for varicella-zoster virus and herpes simplex in Japan and with pritelivir's granted breakthrough therapy designation for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in helicase-primase inhibitors (HPIs)...The asset was contributed to Assembly Biosciences, where it is under development as ABI-1179 at the investigational new drug (IND) enabling stage for high-recurrence genital herpes. A structure proposal for indolinoyl derivative ABI-1179 is presented, showing its potential opportunities and limitations compared to other HPIs."

Journal • Review • Herpes Simplex • Herpes Zoster • Infectious Disease • Varicella Zoster

Advances and Prospect in Herpesviruses infections after Hematopoietic Cell Transplantation: Closer to the Finish Line? (PubMed, Clin Microbiol Infect) - "While considerable advances have been achieved for the treatment and prevention of herpes virus infections, most notably with CMV, the coming years should hold additional opportunities to tame the beast in these herpesviruses post allogeneic HCT, with the advent of new antivirals, cell-mediated immunity testing, and cytotoxic T lymphocytes infusions."

Journal • Review • Cytomegalovirus Infection • Epstein-Barr Virus Infections • Herpes Simplex • Herpes Zoster • Infectious Disease • Transplantation • Varicella Zoster

A Screening Study Identified Decitabine as an Inhibitor of Equid Herpesvirus 4 That Enhances the Innate Antiviral Response. (PubMed, Viruses) - "Aciclovir, the most widely used antiviral against alpha-herpesviruses in vivo, does not appear to be effective against EHV-4 in vitro. Potential antiviral activities were confirmed for eight molecules (idoxuridine, vidarabine, pritelivir, cidofovir, valganciclovir, ganciclovir, aphidicolin, and decitabine). Decitabine demonstrates the highest efficacy against EHV-4 in vitro. Transcriptomic analysis revealed the up-regulation of various genes implicated in interferon (IFN) response, suggesting that decitabine triggers the immune antiviral pathway."

Journal • Preclinical • CNS Disorders • Infectious Disease

Evaluation of the Clinical Drug-Drug Interaction Potential of Pritelivir on Transporters and CYP450 Enzymes Using a Cocktail Approach. (PubMed, Clin Pharmacol Drug Dev) - "In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately...The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential."

Journal • Breast Cancer • Herpes Simplex • Oncology • Solid Tumor • CYP2C9 • CYP3A4 • SLCO2B1

Development and validation of HPLC-ultraviolet method for quantitative determination of pritelivir in human placental perfusion medium. (PubMed, Biomed Chromatogr) - "Pritelivir was stable under the storage and sample handling conditions. This validated HPLC-UV method was utilized to quantify pritelivir in the placental perfusion medium samples, and the resulting concentrations were authenticated with incurred sample reanalysis to confirm the reliability of the method."

Journal

Replacement of sulfonamide by sulfoximine within a helicase-primase inhibitor with restricted flexibility. (PubMed, Bioorg Med Chem Lett) - "Since amenamevir is already approved for varicella-zoster virus (VZV) and HSV in Japan and pritelivir has received breakthrough therapy status for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in me-too approaches. Here, we describe the attempt to improve nervous tissue penetration in Phaeno Therapeutics drug candidate HN0037 to target the latent reservoir of HSV by installing less polar moieties, mainly a difluorophenyl instead of a pyridyl group, and replacing the primary sulfonamide with a methyl sulfoximine moiety. However, all obtained stereoisomers exhibited a weaker inhibitory activity on HSV-1 and HSV-2."

Journal • Herpes Simplex • Herpes Zoster • Infectious Disease • Varicella Zoster

Mass Balance and Metabolite Profile after Single and Multiple Oral Doses of Pritelivir in Healthy Subjects. (PubMed, Clin Pharmacol Drug Dev) - "Only minor metabolites were observed in feces. In conclusion, the major metabolic pathways of pritelivir have been identified with the primary excretion route being renal."

Journal

PRIOH-1: Trial on Efficacy and Safety of Pritelivir Tablets for Treatment of Acyclovir-resistant Mucocutaneous HSV (Herpes Simplex Virus) Infections in Immunocompromised Subjects (clinicaltrials.gov) - P3 | N=153 | Recruiting | Sponsor: AiCuris Anti-infective Cures AG | Trial completion date: Oct 2024 ➔ Apr 2025 | Trial primary completion date: Jun 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Herpes Simplex • Infectious Disease

Helicase-primase inhibitor pritelivir for the treatment of resistant HSV infections in immunocompromised patients (IDWeek 2023) - No abstract available

Clinical • Herpes Simplex • Infectious Disease

Thorough QT/QTc of Pritelivir in Healthy Subjects (clinicaltrials.gov) - P1 | N=64 | Completed | Sponsor: AiCuris Anti-infective Cures AG | Recruiting ➔ Completed

Trial completion • Herpes Simplex • Infectious Disease

Management of aciclovir-resistant mucocutaneous herpes simplex virus infection: a systematic review (BAD 2023) - "These include artesunate, zidovudine, varicella-zoster virus vaccine, leflunomide and surgical excision, which achieved variable response rates but have not been widely studied. While foscarnet and cidofovir have the most robust evidence, IV administration of these agents is associated with significant side-effects and may be limiting. Intralesional and topical formulations of cidofovir, trifluridine and imiquimod are alternative options appropriate for outpatient management. Pritelivir is a novel and promising treatment of mucocutaneous ACV-R HSV infection."

Review • Anemia • Hematological Disorders • Herpes Simplex • Herpes Zoster • Infectious Disease • Renal Disease • Varicella Zoster

Management of aciclovir-resistant mucocutaneous herpes simplex virus infection: a systematic review (BAD 2023) - "These include artesunate, zidovudine, varicella-zoster virus vaccine, leflunomide and surgical excision, which achieved variable response rates but have not been widely studied. While foscarnet and cidofovir have the most robust evidence, IV administration of these agents is associated with significant side-effects and may be limiting. Intralesional and topical formulations of cidofovir, trifluridine and imiquimod are alternative options appropriate for outpatient management. Pritelivir is a novel and promising treatment of mucocutaneous ACV-R HSV infection."

Review • Anemia • Hematological Disorders • Herpes Simplex • Herpes Zoster • Infectious Disease • Renal Disease • Varicella Zoster

Expanded Access Intermediate Size Treatment Protocol: Pritelivir for Immunocompromised Subjects With Treatment Resistant Herpes Simplex Virus Type 1 or 2 (clinicaltrials.gov) - P=N/A | N=N/A | Available | Sponsor: AiCuris Anti-infective Cures AG

New trial • Herpes Simplex

"Aciclovir resistant HSV … difficult to treat and seen post- alloHSCT on valaciclovir prophylaxis. Testing is difficult. Case reports of successful pritelivir use. Trial ongoing. @NCICancer #ECCMID2023" (@michyong2)

Bone Marrow Transplantation • Oncology

Case Commentary: "Salvage Treatment of Refractory HSV Oral Lesions with Pritelivir in Allogeneic Hematopoietic Cell Transplant Recipients" by Bosetti et al. (PubMed, Antimicrob Agents Chemother) - No abstract available

Journal • Bone Marrow Transplantation • Herpes Simplex • Transplantation

Salvage Treatment of Refractory HSV Oral Lesions with Pritelivir in Allogeneic Hematopoietic Cell Transplant Recipients. (PubMed, Antimicrob Agents Chemother) - "No adverse events were noted. Pritelivir appears to be an effective and safe option for the management of acyclovir-r/r HSV infections in highly immunocompromised patients in an outpatient setting."

Journal • Bone Marrow Transplantation • Herpes Simplex • Infectious Disease • Transplantation

First-in-Human, Single- and Multiple-Ascending-Dose, Food-Effect, and Absolute Bioavailability Trials to Assess the Pharmacokinetics, Safety, and Tolerability of Pritelivir, a Nonnucleoside Helicase-Primase Inhibitor Against Herpes Simplex Virus in Healthy Subjects. (PubMed, Clin Pharmacol Drug Dev) - "Pritelivir was safe and well tolerated up to 600 mg following single and up to 200 mg following multiple once-daily doses. Considering a therapeutic dose of 100 mg once-daily, pritelivir demonstrated a favorable safety and tolerability and pharmacokinetic profile in healthy subjects to support further development."

Journal • P1 data • PK/PD data • Herpes Simplex

Salvage treatment of refractory HSV-oral lesions with pritelivir in allogeneic haematopoietic cell transplant recipients (ECCMID 2023) - No abstract available

Clinical • Transplantation

Thorough QT/QTc of Pritelivir in Healthy Subjects (clinicaltrials.gov) - P1 | N=64 | Recruiting | Sponsor: AiCuris Anti-infective Cures AG

New P1 trial • Herpes Simplex • Infectious Disease