HOVILPR Ref.[117015] Active ingredients:

Exposure-Response

No exposure-response relationship was identified between steady-state plasma pritelivir exposures at 100 mg once daily and the occurrence of all lesions healed by Day 28.

Cardiac Electrophysiology

At 4 times the recommended maintenance pritelivir dose, clinically significant QTc interval prolongation was not observed.

The pharmacokinetic properties of pritelivir following oral administration of HOVILPRI are displayed in Table 2.

Table 2. Pharmacokinetic Properties of Priteliv:

C_max and AUC were dose-proportional after single dose administration (20–480 mg) and multiple dose administration (5–400 mg once daily). After multiple dosing of 100 mg once daily, steady state was reached within 8 days. When a loading dose of 400 mg pritelivir was administered on Day 1 followed by a maintenance dose of 100 mg once daily, steady-state exposures were reached on Day 2. Plasma concentrations at steady state are approximately 5-fold higher than those after single dose administration.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of pritelivir based on age (19 to 84 years), gender, race (including American Indian/Alaska Native, Asian, Black/African American, White, or other), body weight (48 to 176 kg), or underlying immunocompromised condition (including HIV/AIDS, oncology, transplant, or autoimmune/inflammatory disorder).

Patients with Renal Impairment

In a single-dose pharmacokinetic study, pritelivir exposure (AUC and C_max) was comparable between participants with mild (eGFR 60–89 mL/min) or moderate (eGFR 30–59 mL/min) renal impairment and those with normal renal function (eGFR ≥90 mL/min). Pritelivir exposure (AUC and C_max) were approximately 1.6-fold higher in participants with severe renal impairment (eGFR 15–29 mL/min, not on hemodialysis) relative to those with normal renal function. Pritelivir pharmacokinetics in patients on hemodialysis is unknown.

Patients with Hepatic Impairment

In a single-dose pharmacokinetic study, pritelivir exposure (AUC and C_max) was comparable in participants with moderate hepatic impairment (Child-Pugh Class B) relative to those with normal hepatic function. The effect of severe hepatic impairment (Child-Pugh Class C) on pritelivir pharmacokinetics is unknown.

Drug Interactions

Clinical Drug Interaction Studies

Effect of Other Drugs on the Pharmacokinetics of Pritelivir:

Proton pump inhibitors (PPIs): Co-administration of a single oral dose of 100 mg pritelivir (on Day 1) with esomeprazole 40 mg once daily (from Day -3 to Day 1; 4 days total) decreased C_max by approximately 76% and AUC by approximately 59% compared to pritelivir administered alone [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Drug Interactions (7.2)].

In the Phase 3 trial (PRIOH-1, Parts C-F), pritelivir exposures were evaluated for participants who received concomitant omeprazole or lansoprazole (≤20 mg daily), pantoprazole (≤40 mg daily), or an H2-receptor antagonist (with pritelivir administered at least 2 hours before or 12 hours after the H2-receptor antagonist). Pritelivir exposures in participants receiving these acid-reducing agents were not clinically meaningfully different from those in participants who did not receive any acid-reducing agents [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Drug Interactions (7.2)].

Table 3. Changes in Pharmacokinetics of Pritelivir in the Presence of Co-administered Drugs:

Effect of Pritelivir on the Pharmacokinetics of Other Drugs:

BCRP substrates: Co-administration of multiple pritelivir doses (400 mg on Day 1 followed by 100 mg once daily on Day 2 and Day 3) with a single 20 mg oral dose of rosuvastatin (on Day 3) resulted in a 1.7-fold increase in C_max and a 1.4-fold increase in AUC of rosuvastatin compared to rosuvastatin administered alone [see Drug Interactions (7.1)].

Table 4. Changes in Pharmacokinetics of Co-administered Drugs in the Presence of Pritelivir:

CYP2B6, CYP2C8, CYP2C9, CYP3A4, and OATP2B1 substrates: No clinically significant changes in substrate exposures were observed in clinical drug-drug interaction trials when pritelivir was co-administered with the cytochrome P450 (CYP)2B6 substrate bupropion, the CYP2C8 substrate repaglinide, the CYP2C9 substrate flurbiprofen, the CYP3A4 substrate midazolam, and the organic anion transporting polypeptide (OATP)2B1 substrate celiprolol.

In Vitro Drug Interaction Studies

CYP enzymes: As pritelivir is primarily metabolized by non-enzymatic hydrolysis, leading to the formation of AIC090015 and AIC090105, clinically relevant drug-drug interactions with pritelivir as a CYP enzyme substrate are not expected. Pritelivir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at clinically relevant exposures. Pritelivir does not cause clinically relevant induction of CYP1A2, CYP2C9, or CYP2C19. Pritelivir does not cause time-dependent inhibition of any CYP enzymes.

Transporters: Pritelivir is a substrate of both P-glycoprotein (P-gp) and BCRP efflux transporters in vitro, but is not a substrate of OATP1B1, OATP1B3, OATP2B1, organic cation transporter (OCT)1, or organic anion transporter (OAT)1. Because pritelivir has a high absolute oral bioavailability of 72%, co-administration of Pgp or BCRP inhibitors is not expected to impact the oral absorption of HOVILPRI to a clinically relevant extent. Pritelivir does not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K at clinically relevant exposures.

Metabolites: The major circulating metabolites of pritelivir, AIC090015 and AIC090105, are not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 to a clinically relevant extent. No clinically significant differences in the pharmacokinetics of OAT substrates are predicted when coadministered with HOVILPRI 100 mg once daily.

Mechanism of Action

Pritelivir is a HSV helicase-primase inhibitor. It is active against both HSV types, HSV-1 and HSV-2, and prevents de novo synthesis of virus deoxyribonucleic acid (DNA) through inhibition of the viral helicaseprimase complex. Kinetic analysis of the enzyme complex pUL5-pUL52-6xHis revealed the IC50 value of 30 nM.

Antiviral Activity

Pritelivir exhibits an apparent 50% effective concentration (EC50 value) between 0.01 µM and 0.07 µM in cell culture infected with HSV-1 or HSV-2 (laboratory strains and clinical isolates), depending on cell type, virus strain/isolate, and method used. The median EC50 values of pritelivir were 26 nM (average 26 nM, range 10-45 nM, n=27) and 24 nM (average 30 nM, range 7-70 nM, n=32) against HSV-1 and HSV-2 clinical isolates, respectively.

Viral Resistance

In Cell Culture

Pritelivir-resistant HSV-1 and HSV-2 strains were isolated in cell culture with mutations in the viral helicase (UL5) and primase (UL52) genes. In cell culture the following resistance-associated amino acid substitutions were observed (Table 5).

Table 5: Summary of Pritelivir Resistance-associated Amino Acid Substitutions in Cell Culture:

In Clinical Trials

In the PRIOH-1 Phase 3 trial (NCT 03073967) in immunocompromised participants, viral sequence analysis was performed on samples obtained from pritelivir-treated participants who did not heal on pritelivir treatment and for whom on-treatment samples were available for analysis. Paired baseline and on-treatment/end-oftreatment sequences were obtained for 8.3% (4/48) of pritelivir-treated participants who experienced treatment failure (lesions not healed by Day 28). The pUL5 K356N (>1,000-fold reduction in susceptibility in cell culture) substitution was detected in 1 participant infected with HSV-1. The pUL5 K355R (50-fold reduction, 2 participants) and pUL5 N341K, pUL5 G351R (distinct viral subpopulations, 33-fold reduction, 1 participant) substitutions were detected in participants infected with HSV-2. In the PRIOH-1 Phase 2 trial (NCT 03073967), the pUL5 K355T (12-fold reduction, 1 participant) substitution was detected in a participant infected with HSV2.

In another study, the HSV-1 pUL5 N342K (38-fold reduction) + G352C (fold reduction not available) + K356R (fold reduction not available) + pUL52 A899T (100-fold reduction) substitutions were detected in one participant one week after pritelivir discontinuation.

Cross Resistance

Cross resistance is not likely with acyclovir, penciclovir, or foscarnet. Pritelivir retains activity against nucleoside analogue-resistant (e.g., acyclovir) and foscarnet-resistant HSV strains with TK or DNA polymerase substitutions. Substitutions leading to pritelivir resistance do not affect susceptibility to nucleoside analogs and foscarnet.

Carcinogenesis

Carcinogenicity studies with pritelivir are ongoing.

Mutagenesis

Pritelivir free base and pritelivir mesylate monohydrate were not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium, micronucleus tests with cultured mammalian cells, and in the rodent micronucleus assay.

Impairment of Fertility

In fertility studies in rats, doses of pritelivir at 50, 150, or 500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 7 of pregnancy. Males were dosed with 50, 150, or 500 mg/kg/day for 4 weeks before mating and through mating for up to 10 weeks total. Treatment related effects on male fertility including an increase in fetal loss, reduced sperm counts, and morphological and functional deficits in sperm were evident in rats at 500 mg/kg/day because of progressive disturbances to the primary and secondary sex organs. At 150 mg/kg/day, male rats exhibited slight reduction of epididymal sperm counts as well as minor changes in sperm morphology. These effects were no longer apparent after a 6-week recovery, indicating full reversibility. There were no effects on fertility, mating or early embryonic development in females dosed with 150 mg/kg/day and males at 50 mg/kg/day resulting in systemic pritelivir exposures (AUC) approximately 6-times the human exposure at the therapeutic dose of 100 mg. Of note, no effects on the reproductive organs or semen were seen in male sexually mature monkeys over a 39-week treatment period with 1,000 mg/kg/day.

Repeat-dose rodent

In a 26-week oral toxicity study in rats at 10, 50, 250 mg/kg/day, early stages of lenticular opacity (cataracts) and vitreous floaters in the eye were observed at 250 mg/kg/day. In a 13-week mouse toxicity study at 100, 500, 1,500 mg/kg/day, lenticular opacity and compound depositions were noted at ≥500 mg/kg/day. No ocular findings occurred in the rat and mouse at systemic exposures (AUC) approximately 28- (rats) and 14- (mice) times the human exposure at the therapeutic dose of 100 mg. Further, no ocular findings were apparent in the monkey with up to 39 weeks of treatment at 1,000 mg/kg/day.

14.1 Immunocompromised Adults with Mucocutaneous HSV Infection that is Refractory (with or without Documented Resistance) to Treatment with Acyclovir, Valacyclovir, or Famciclovir (PRIOH-1)

The efficacy of HOVILPRI was evaluated in a randomized, open-label, comparator-controlled, superiority trial (PRIOH-1 Phase 3 Trial, Part C; NCT 03073967) in immunocompromised participants with mucocutaneous (mucosal and/or cutaneous lesions) HSV infection that was refractory (with or without documented resistance) to treatment with acyclovir, valacyclovir, or famciclovir. Participants with ocular, CNS, or disseminated HSV disease were not enrolled. Participants received HOVILPRI (400 mg loading dose on Day 1 followed by 100 mg once daily) or Investigator's Choice treatment (IV foscarnet, IV/topical cidofovir, or 5% topical imiquimod) for up to 28 days until all mucocutaneous lesions healed, extended up to 42 days total if lesions were improving but not completely healed after 28 days. Refractory HSV infection (clinical failure) was defined as no clinical improvement after at least 7 days of standard-of-care nucleoside analogue treatment [acyclovir (ACV), valacyclovir (VACV) or famciclovir (FCV)], with or without laboratory confirmed genotypic/phenotypic resistance for the current HSV outbreak.

A total of 101 participants (≥18 years) were randomized 1:1 and treated with HOVILPRI (N = 51) or Investigator's Choice (N =50). The mean age of participants was 53 years (range 19-84 years), 53% were male. Race and ethnicity were as follows: 49% White, 23% Black/African American, 16% American Indian/Alaska native, 10% other, and 3% Asian; 26 % were of Hispanic/Latino ethnicity.

At enrollment, the majority of participants, 71%, had refractory HSV infection and 29% had laboratory confirmed ACV resistance. Participants represented a wide range of immunosuppressive clinical conditions, including one or more of the following underlying conditions: hematologic malignancy/disorder (47%), hematopoietic stem-cell transplantation (40%), HIV infection (38%), autoimmune/inflammatory diseases (29%), non-hematologic malignancies (26%) or solid-organ transplantation (4%). The most common treatment used in the Investigator's Choice arm was IV foscarnet (70%), followed by topical 5% imiquimod (14%), IV cidofovir (12%), and topical cidofovir (4%).

Efficacy Results

The primary efficacy endpoint was the proportion of participants with all lesions healed with complete epithelization, as assessed by the Investigator, (response rate) during the treatment period up to 28 days. Because HSV establishes lifelong latent infection, treatment is not curative. The primary efficacy result from PRIOH-1 is displayed in Table 8.

Table 6. Primary Efficacy Result in PRIOH-1, Part C:

The secondary endpoint was the response rate up to 42 days. The observed response rates were 82% treated with HOVILPRI vs. 42% with Investigator's Choice, with an adjusted treatment difference of 40% (95% CI: 22.7, 57.7). 33 % of participant in the HOVILPRI arm extended treatment up to 42 days, whose lesions were improving by Day 28.

The efficacy of HOVILPRI was further evaluated in Parts D and F of Trial PRIOH-1, which had a nonrandomized, open-label, single-arm design to assess the efficacy and safety of HOVILPRI (400 mg loading dose on Day 1 followed by 100 mg once daily). Enrolled participants were immunocompromised and had acyclovir/foscarnet (ACV/FOS) refractory HSV infection or were FOS intolerant (N=35). Underlying immunosuppressive conditions included hematologic malignancy/disorder, hematopoietic stem-cell transplantation, non-hematologic malignancies, HIV infection, autoimmune/inflammatory diseases and solidorgan transplantation. Treatment with HOVILPRI resulted in lesion healing in 40% (95% CI: 23.9, 57.9) of participants during the treatment period up to 28 days and 66% (95% CI: 47.8, 80.9) of participants up to 42 days.