Section 4 of 6
Clinical evidence 1080 evidence topics · 77 sources
3.1.1 PRIOH-1 parts C to F
Study aim stated in the first congress presentation of Part C Objective stated in the congress abstract Part C: superiority objective in the ClinicalTrials.gov record Main objectives of Parts C, D, and F in the EU Clinical Trials Register record Secondary objectives of Parts C, D, and F in the EU Clinical Trials Register record Part E: main objective in the EU Clinical Trials Information System record Parts D and F: purpose stated in the prescribing information Aim stated in the company release of topline results Aim stated in the company release on completion of enrollment 3.1.1.2 Location and study date
Study dates and status in the ClinicalTrials.gov record Start of the phase 3 part Number of locations in the ClinicalTrials.gov record Study locations in the ClinicalTrials.gov record Countries and number of participants as reported in the release on completion of enrollment Countries and number of participants as reported in the release of topline results Sites and countries as reported on the trial-in-progress congress poster Sites and countries as reported in the company corporate presentation Sites and regions planned at the start of the phase 3 part European Union member states, trial dates, and recruitment dates Overall trial dates in the EU Clinical Trials Information System record Planned sites and regions in the EU Clinical Trials Register record
Prescribing information: design of Part C Prescribing information: design of Parts D and F FDA approval announcement: design of Part C Parts of the trial in the ClinicalTrials.gov record Part C: randomized comparison in the ClinicalTrials.gov record Part D: design in the ClinicalTrials.gov record Part E: design in the ClinicalTrials.gov record Part F: design in the ClinicalTrials.gov record Design details in the ClinicalTrials.gov record Arms in the ClinicalTrials.gov record Phase 3 design and planned arm sizes on the trial-in-progress congress poster Design fields in the EU Clinical Trials Register record Assessment of lesion healing by the investigator Addition of the phase 3 part to the phase 2 trial by amendment Change in the control arm design between protocol versions Follow-up visits and telephone contacts in the ClinicalTrials.gov record Sponsorship and medical writing support 3.1.1.4 Eligibility criteria
Prescribing information: population, definition of refractory infection, and excluded disease forms Part C inclusion criteria in the ClinicalTrials.gov record Age eligibility as stated in each source Eligible immunocompromising conditions in the congress abstract Key inclusion criteria in the congress presentation Definitions of refractory and resistant infection shown in the congress presentation Resistance testing by the local laboratory Part C exclusion criteria in the ClinicalTrials.gov record “Known resistance/intolerance to pritelivir or any of the excipients.” (opens the source at this quote in a new tab) Copy Flag
“Previous treatment in PRIOH-1.” (opens the source at this quote in a new tab) Copy Flag
“Baseline safety laboratory abnormalities.” (opens the source at this quote in a new tab) Copy Flag
“History or current evidence of gastrointestinal malabsorption which, in the opinion of the Investigator, may affect the extent of absorption of pritelivir.” (opens the source at this quote in a new tab) Copy Flag
“Hemodialysis for any indication and ESRD (eGFR <15 mL/min; stage 5 CKD)” (opens the source at this quote in a new tab) Copy Flag
“History or current evidence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other relevant diseases.” (opens the source at this quote in a new tab) Copy Flag
“Pregnant and/or breastfeeding women.” (opens the source at this quote in a new tab) Copy Flag
Part C exclusion criteria: laboratory thresholds in the EU Clinical Trials Register record Part C exclusion criteria: other conditions in the EU Clinical Trials Register record Parts D and F: inclusion criterion replacing the Part C resistance criterion Parts D and F: definitions of foscarnet failure and foscarnet intolerance “Clinical failure of foscarnet treatment is defined as no improvement after at least 7 days of foscarnet iv therapy. For subjects coming from Part C due to clinical failure of foscarnet, clinical failure is defined as discontinuation and/or replacement of foscarnet after at least 7 days of treatment due to worsening of lesion(s) and/or appearance of new lesion(s).” (opens the source at this quote in a new tab) Copy Flag
“Manifestations of foscarnet intolerance may include, impairment of renal function, seizures, genital irritation and/or ulcerations, extremity paresthesia, nausea, granulocytopenia, anemia, leukopenia, thrombopenia, hypokalemia, hypocalcemia, hypomagnesemia, diabetes insipidus, injection site reactions, psychiatric disorders, including but not limited to anxiety and aggression.” (opens the source at this quote in a new tab) Copy Flag
Parts D and F: exclusion criteria Part E: inclusion and exclusion criteria in the ClinicalTrials.gov record
Prescribing information: regimens and treatment duration in Part C Pritelivir dose and rationale for the loading dose in the ClinicalTrials.gov record Comparator options and doses in the ClinicalTrials.gov record Treatment duration and extension in the ClinicalTrials.gov record Comparator described in the release of topline results Prescribing information: treatments received in the investigator's choice arm Treatments received in the investigator's choice arm, full analysis population Extent of exposure in days by treatment received, full analysis population Prescribing information: duration of pritelivir treatment and share with extended treatment Treatments received in the investigator's choice arm, HIV subgroup Antiretroviral therapy in the HIV subgroup Protocol specification for acid-reducing agents Parts D and F: pritelivir regimen and washout after foscarnet Part E: pritelivir regimen in the ClinicalTrials.gov record Non-randomized parts: regimen described in a company release
3.1.1.6.1 Rationale for using healing of all lesions within 28 days as the primary endpoint
Prescribing information: primary efficacy endpoint Prescribing information: treatment is not curative Primary outcome measure in the ClinicalTrials.gov record Primary endpoint in the EU Clinical Trials Register record: cure, failure, and indeterminate response Primary endpoint as worded in the congress presentations Lesion healing as the endpoint carried over from the phase 2 part Prescribing information: secondary endpoint Secondary efficacy outcome measures in the ClinicalTrials.gov record Secondary endpoints of Part C in the EU Clinical Trials Register record: recurrence, pain scale, and resistance Secondary endpoints as listed in the congress presentations Endpoints as listed on the trial-in-progress congress poster “Primary Endpoint: healing rate (Day 28)” (opens the source at this quote in a new tab) Copy Flag
“Efficacy endpoints includes healing rate (Day 42), time to lesion healing and cessation of shedding, pain scores, shedding rate, therapy failure rate, and resistance rate” (opens the source at this quote in a new tab) Copy Flag
“Safety/tolerability endpoints includes AEs, SAEs, discontinuation, AEs of special interest, labs, ECGs, vital signs, discontinuation rates” (opens the source at this quote in a new tab) Copy Flag
“PK and Quality of Life” (opens the source at this quote in a new tab) Copy Flag
Secondary safety outcome measures in the ClinicalTrials.gov record Viral DNA endpoints: detection limit and definition of the detection rate 3.1.1.7 Statistical analysis description
3.1.1.7.1 Number of participants (Planned and analyzed)
Sample size calculation for Part C Planned number of participants by part on the trial-in-progress congress poster Planned number of participants in the EU Clinical Trials Register record Planned enrollment announced at the start of the phase 3 part Planned enrollment in the company corporate presentation Enrollment as reported on the trial-in-progress congress poster Enrollment as reported in the release on completion of enrollment Enrollment as reported in the release of topline results Enrollment as reported on the registry Randomized and non-randomized participants as reported in later company releases Participants randomized, treated, and analyzed in Part C Prescribing information: participants randomized and treated in Part C and enrolled in Parts D and F Prescribing information: size of the pritelivir safety database 3.1.1.7.2 Description of analysis sets
Analysis population of the primary efficacy result in the prescribing information Definition of the overall population in the congress presentation Analysis sets and handling of indeterminate responses in the EU Clinical Trials Register record Denominator of the cure rate in the ClinicalTrials.gov record Primary analysis: stratified test and confidence interval method Stratification factor of the primary analysis in the congress presentations Significance level and power of the planned comparison Subgroup analyses: unadjusted difference, exact confidence interval, and minimum subgroup size Subgroup analyses described as pre-defined HIV subgroup analysis described as post hoc Classification of participants by underlying disease and by immunosuppressive condition Definition of baseline and of laboratory-confirmed acyclovir resistance Viral DNA analyses: population, censoring, and models Resistance analyses: participants tested Safety analysis population
3.1.1.8.1 Participant disposition
Part C: disposition by arm Part C: other reasons for not completing treatment in the investigator's choice arm Part C: participants randomized and participant not treated Part C: completion of treatment as summarized in the congress presentation Prescribing information: participants randomized and treated Prescribing information: participants with treatment extended beyond day 28 HIV subgroup: disposition by arm HIV subgroup: other reasons for not completing treatment in the investigator's choice arm HIV subgroup: completion of treatment as reported in the company release Parts D, E, and F: participants treated Parts D, E, and F: completion and discontinuation No evidence found.
3.1.1.8.2 Baseline characteristics
Prescribing information: age, sex, race, and ethnicity Prescribing information: refractory infection, laboratory-confirmed resistance, and underlying conditions Demographics and baseline characteristics by arm, full analysis population Underlying disease by arm, with participants counted under each applicable condition Immunosuppressive condition by arm, with each participant counted once by hierarchy Share of participants living with HIV as reported in the conference abstract Share of participants living with HIV as reported in the company release Immunocompromising conditions as reported in the journal abstract HIV subgroup: demographics and baseline characteristics by arm HIV subgroup: participants with a CD4 count below 200 cells/mm3 HIV subgroup: other underlying conditions Lesion site at baseline No evidence found.
Parts D and F: underlying immunosuppressive conditions Part E: baseline characteristics No evidence found.
3.1.1.8.3 Efficacy results
Primary endpoint: all lesions healed up to day 28, prescribing information Primary endpoint as reported in the FDA approval announcement Primary endpoint as reported in the congress presentation Primary endpoint as reported in the journal abstract Secondary endpoint: all lesions healed up to day 42, prescribing information Lesion healing up to day 28 and up to day 42, congress presentation Lesion healing up to day 42 as reported in the company releases Unadjusted treatment difference in the full analysis set Subgroups by region, sex, age, and race: lesion healing up to day 28 Subgroups by region, sex, age, and race: lesion healing up to day 42 Subgroups by immunocompromised condition: lesion healing up to day 28 Subgroups by immunocompromised condition: lesion healing up to day 42 Pritelivir against each investigator's choice treatment: lesion healing up to day 28 Pritelivir against each investigator's choice treatment: lesion healing up to day 42 Subgroups by laboratory-confirmed acyclovir resistance: lesion healing up to day 28 and up to day 42 HIV subgroup, all participants living with HIV: lesion healing up to day 28 and up to day 42 HIV subgroup, all participants living with HIV: result and confidence interval in the company release HIV subgroup, participants classified under HIV infection by hierarchy: result in the conference abstract Time to lesion healing, recurrence, and treatment failure rate No evidence found.
Viral DNA: time to undetectable HSV DNA in lesion swabs Viral DNA: participants at risk in the analysis of time to undetectable HSV DNA Viral DNA: mean detection rate in lesion swabs and cessation of detection Resistance outcomes: prescribing information Resistance outcomes: congress presentation Parts D and F: lesion healing up to day 28 and up to day 42 Part E: efficacy results No evidence found.
3.1.1.8.4 Health-related quality of life and patient-reported outcomes
Patient-reported pain endpoints specified for Part C Quality of life listed among the trial assessments Results for pain and quality-of-life endpoints No evidence found.
Prescribing information: adverse reactions and discontinuations in Part C Prescribing information: hepatic laboratory abnormalities in Part C Prescribing information: duration of exposure in Part C Overview of adverse events by arm, safety population Adverse events of special interest by arm, including renal and electrolyte events Treatment-emergent adverse events with an incidence of 5% or more, by preferred term Adverse events among reasons for not completing treatment, by arm Deaths and foscarnet intolerance among reasons for not completing treatment in the investigator's choice arm Safety summary in the journal abstract Most common adverse events with pritelivir as reported in the company release Safety as summarized in the FDA approval announcement Parts D and F: safety in the prescribing information Part E: safety results No evidence found.
Summary Part C was open-label, and the investigator assessed lesion healing. The comparator was the investigator's choice among four regimens; 35 of 50 comparator participants (70%) received intravenous foscarnet, and the control arm design changed between protocol versions. The trial randomized 102 participants and analyzed 101; confidence intervals for several subgroups include zero, and the analysis of all 38 participants with HIV was post hoc. In the comparator arm, 23 of 50 participants (46%) did not complete treatment. Parts D and F were single-arm with 35 participants, and no result for Part E was located. As of October 2026, Part C results come from the prescribing information, congress presentations and abstracts, and company releases; no full peer-reviewed publication was found, and the ClinicalTrials.gov record has no posted results. Sources differ on total enrollment (153, 157, or 158). The share of participants with HIV is 37.6% (38 of 101) when each participant is counted under every underlying disease and 22.8% (23 of 101) when each is counted once by hierarchy.
Open-label design and investigator assessment of the primary endpoint Comparison of adverse reaction rates across trials Disease forms excluded from enrollment Subgroup comparisons limited by subgroup size Paired sequences available for resistance analysis Results posting on the registry 3.1.2 PRIOH-1 parts A and B
Primary objective: efficacy of oral pritelivir against intravenous foscarnet in Part A Secondary objectives: safety in Part A, and efficacy and safety in Part B Scope of the publication within the phase 2/3 trial Objective stated in the congress abstract Objective stated by the sponsor when the first site opened 3.1.2.2 Location and study date
First site opening and planned number of sites, sponsor release at trial initiation Number of sites as reported in the sponsor release on the phase 3 start Registry record: protocol number, start date, and status of the phase 2 parts European Union trial number named with the phase 2 results Congress presentation of the phase 2 results
Two parts within the phase 2 portion of a phase 2/3 trial Randomization ratio and open-label allocation Transfer from Part A to Part B and washout Lesion assessment: index lesion, standardized photography, blinded review, and participant diary Virologic sampling, central laboratory testing, and resistance testing Safety monitoring and grading of adverse events Treatment and follow-up periods shown in the congress slides Trial conduct, consent, and safety oversight Registry description of Parts A and B “The trial comprises 5 Parts, Part A, B, C, D, E and F.” (opens the source at this quote in a new tab) Copy Flag
“Part A is a randomized, open-label, multi-center, comparative design to assess the efficacy and safety in subjects with ACV-resistant mucocutaneous HSV infection, treated with oral pritelivir or intravenous foscarnet.” (opens the source at this quote in a new tab) Copy Flag
“Part B is an open-label, multi-center design to assess the efficacy and safety of pritelivir in subjects with ACV-resistant-mucocutaneous HSV and who either:” (opens the source at this quote in a new tab) Copy Flag
“present with foscarnet-resistance/intolerance, or” (opens the source at this quote in a new tab) Copy Flag
“developed foscarnet resistance/intolerance during treatment in Part A (no improvement after at least 5 days of foscarnet therapy or intolerance to foscarnet requiring cessation of foscarnet treatment).” (opens the source at this quote in a new tab) Copy Flag
Design as announced by the sponsor at trial initiation Amendment of the trial to add the phase 3 part 3.1.2.4 Eligibility criteria
Population common to both parts Part A: acyclovir-refractory infection with or without resistance Part B: additional foscarnet refractoriness, resistance, or intolerance Key inclusion criteria as presented in the congress slides Registry description of the Part B population Definition of refractory infection given in the article's introduction Consensus definitions of refractory and resistant infection shown in the congress slides Relation of the enrolled population to the consensus definitions
Pritelivir regimen in Parts A and B Intravenous foscarnet regimen in Part A Regimens as stated in the congress abstract Regimens as shown in the congress slides Duration of treatment exposure in Part A Foscarnet as a prohibited concomitant medication in Part B Pritelivir regimen as described in the sponsor release on the congress presentation Pritelivir regimen as described in the congress case series of the phase 2 participants
3.1.2.6.1 Rationale for using time to lesion healing as the primary endpoint
Primary endpoint: definition, censoring, and confirmation by independent photographic review Rationale for the primary endpoint Primary endpoint as announced at trial initiation Secondary efficacy endpoints: investigator-assessed time to healing, healing rate, and HSV DNA Endpoints as listed in the abstract of the publication Independent photographic review compared with investigator assessment Choice of investigator-assessed healing rate as the endpoint for phase 3 Endpoints as presented in the congress slides Healing rate as defined in the congress abstract Virologic outcome: threshold for a positive swab Resistance outcome: participants tested Safety outcomes: adverse events of special interest 3.1.2.7 Statistical analysis description
3.1.2.7.1 Number of participants (Planned and analyzed)
Basis for the planned sample size Participants screened, enrolled, and treated Reason enrollment ended below the planned number Participants in each analysis set of the publication's tables Participants as reported in the abstract of the publication Participants as reported in the congress abstract Participants as reported in the sponsor release on the congress presentation Pritelivir recipients pooled across both parts in the congress slides 3.1.2.7.2 Description of analysis sets
Full analysis set and primary data source Primary analysis: log-rank test, Kaplan-Meier estimates, and Cox model Censoring in the time-to-healing analysis Analysis of secondary efficacy outcomes Values reported as not estimable Confidence intervals and tests named in the efficacy table footnotes Counting rule for adverse events
3.1.2.8.1 Participant disposition
Screening, enrollment, and allocation Part A: treatment completion and discontinuation by arm Part B: treatment discontinuation Discontinuation because of adverse events, congress slides Early discontinuation in the congress case series of the phase 2 participants 3.1.2.8.2 Baseline characteristics
Baseline demographics and clinical characteristics, full analysis set Part A: comparability of the arms, race, and virus type Part A: absolute neutrophil count and prior anti-HSV treatment Part A: cause of immunosuppression by arm Part B: characteristics compared with pritelivir recipients in Part A Mean age as presented in the congress slides Cause of immunosuppression across both parts, congress abstract Underlying conditions in the congress case series of the phase 2 pritelivir recipients 3.1.2.8.3 Efficacy results
Primary endpoint in Part A: time to lesion healing by independent photographic review Time to lesion healing through the last study visit in Part A Primary and selected secondary efficacy endpoints in Part A, full analysis set Healing rate by independent photographic review in Part A Healing rate and time to healing by investigator assessment in Part A HSV DNA detection in lesion swabs in Part A Resistance to trial medication in Part A Authors' discussion of the K355T substitution Prescribing information: susceptibility reduction with the substitution detected in the phase 2 trial Resistance rates among participants tested after treatment, congress poster Lesion recurrence during follow-up in Part A Part B: time to healing, healing rate, and recurrence Part B: viral detection and resistance Results as summarized in the abstract of the publication “In Part A, median time to healing was 26.0 days (95% CI, 13.0–31.0) with pritelivir, vs not estimable (95% CI, 20.0–NE) with foscarnet (HR, 2.7; 95% CI, 0.33–21.8; P = .34). Investigator-assessed healing rates were 93% with pritelivir and 57% with foscarnet, a 36.2% difference (95% CI, −10.1 to 74.1; P = .077). Postbaseline HSV DNA detection rates were 34.8% and 50.0%, respectively (P = .42).” (opens the source at this quote in a new tab) Copy Flag
“In Part B, the median time to healing was 19.0 days, with a 63% healing rate.” (opens the source at this quote in a new tab) Copy Flag
Lesion healing rates with confidence intervals, congress slides Healing rates as reported in the congress abstract Healing rates as reported in sponsor releases Healing across all 23 pritelivir recipients, congress case series Overall proportion of pritelivir recipients with full lesion resolution, congress poster Authors' interpretation of the efficacy results 3.1.2.8.4 Health-related quality of life and patient-reported outcomesNo evidence found.
Part A: adverse events, serious adverse events, and severity by arm Part A: overview of treatment-emergent adverse events, safety analysis set Part A: treatment-emergent adverse events of special interest, safety analysis set Part A: adverse events with an incidence of 10% or more in either arm, by preferred term Part A: most common adverse events by arm Part A: renal events and electrolyte abnormalities Part A: hematologic, coagulation, and cutaneous events of special interest Part A: adverse events leading to discontinuation Part A: vital signs, electrocardiogram, and laboratory parameters Part B: adverse events, serious adverse events, and deaths Part B: most frequent adverse events, including increased creatinine Part B: events of special interest, vital signs, and laboratory parameters Authors' discussion of tolerability and events of special interest Safety as summarized in the abstract of the publication Overview of safety findings in Part A, Part B, and all pritelivir recipients, congress slides Drug-related treatment-emergent adverse events by system organ class, congress slides Safety conclusions in the congress slides Treatment-related adverse events and discontinuations by part, congress poster Discontinuation because of adverse events as reported in the congress abstract Discontinuation because of adverse events as reported in sponsor releases Tolerability in the congress case series of the phase 2 pritelivir recipients
Summary Part A randomized 22 participants (15 to pritelivir, 7 to foscarnet) against a planned 30, after the sponsor ended phase 2 to begin phase 3; Part B treated 8 participants without a comparator. Treatment was open label, and the trial was not designed or powered to detect statistical differences. The primary endpoint did not differ significantly (hazard ratio 2.70; 95% CI 0.33 to 21.83; P = .34). Healing was recorded in 10 of 15 pritelivir recipients by independent photographic review and in 14 of 15 by investigators. Five of 7 foscarnet recipients stopped treatment early. The arms differed in race and in cause of immunosuppression, which was not a stratification factor. AiCuris funded the trial and employs three authors.
Limitations stated by the authors Interpretation of the primary endpoint limited by sample size Statistical power as stated in the congress slides Enrollment ended below the planned number Collection of adverse events of special interest Confirmation sought in the phase 3 parts Funding, sponsor employment of authors, and medical writing support
Aim stated in the publication Aim stated in the registry record Secondary objective: monitoring for molecular signals of drug resistance 3.1.3.2 Location and study date
Sites and conduct period in the publication Study dates and status in the registry record Study locations in the registry record
Randomized, parallel, double-blind, placebo-controlled design Randomization ratio, method, and stratification Daily genital swabs, symptom diary, and clinic visits for recurrences HSV DNA assay, positivity threshold, and threshold for resistance sequencing Safety evaluation and adverse event grading Design fields in the registry record Statistical analysis responsibility, data access, and funding Resistance sequencing substudy: regions sequenced and sample thresholds Mathematical modeling study of the trial's shedding data: purpose 3.1.3.4 Eligibility criteria
Inclusion criteria in the publication Exclusion criteria and prohibited concomitant treatments in the publication Inclusion criteria in the registry record Exclusion criteria in the registry record Age, sex, and healthy volunteer fields in the registry record
Four oral pritelivir regimens and placebo for 28 days Arm descriptions in the registry results Loading doses by arm as described in the modeling study Adherence to swab collection and study medication
3.1.3.6.1 Rationale for using genital HSV shedding rate as the primary endpoint
Primary endpoint defined in the publication Primary outcome measure in the registry record Rationale given by the investigators for a shedding endpoint Lesion endpoints in early-phase trials of HSV antivirals Surrogate outcome analysis: question and data sources Correlation of shedding rate with lesion rate in a natural history cohort Proportion of the pritelivir effect on recurrences and lesions explained by shedding Conclusion of the surrogate outcome analysis Limits of shedding as a surrogate outcome 3.1.3.7 Statistical analysis description
3.1.3.7.1 Number of participants (Planned and analyzed)
Participants screened, randomized, and treated Enrollment in the registry record Participants started and in the full analysis set by arm, registry results Swabs and participants contributing to the shedding analysis Swab specimens available to the resistance sequencing substudy Participant count as described in the modeling study 3.1.3.7.2 Description of analysis sets
Intention-to-treat analysis population Statistical model for shedding and lesion rates Comparison of HSV DNA quantity and concordance of swab sources Baseline analysis population in the registry results Resistance sequencing substudy: participants and acceptance rule Modeling study: outcome definitions and comparisons between arms
3.1.3.8.1 Participant disposition
Completion and reasons for discontinuation in the publication Reason for ineligibility at screening Participant flow by arm in the registry results Reasons for not completing by arm in the registry results 3.1.3.8.2 Baseline characteristics
Age, sex, race, duration of genital herpes, and prior suppressive therapy Demographics by arm in the registry results, full analysis set Characteristics of the placebo and 75 mg daily arms combined, from a later analysis of the trial data 3.1.3.8.3 Efficacy results
Primary endpoint: genital HSV shedding rate by dose “The rate of HSV shedding in the placebo group was 16.6%; among the groups receiving pritelivir daily, the rate was 18.2% with 5 mg, 9.3% with 25 mg, and 2.1% with 75 mg; in the group receiving 400 mg weekly, the rate was 5.3% (Table 2 and Figure 1A).” (opens the source at this quote in a new tab) Copy Flag
“The relative risk of viral shedding with pritelivir as compared with placebo was 1.11 (95% confidence interval [CI], 0.65 to 1.87; P=0.70) at a daily dose of 5 mg, 0.57 (95% CI, 0.31 to 1.03; P=0.06) at a daily dose of 25 mg, 0.13 (95% CI, 0.04 to 0.38; P<0.001) at a daily dose of 75 mg, and 0.32 (95% CI, 0.17 to 0.59; P<0.001) at a weekly dose of 400 mg (Table 2).” (opens the source at this quote in a new tab) Copy Flag
Primary outcome in the registry results: mean per-participant shedding rate Quantity of HSV DNA on days with detection Subclinical shedding rate by dose “The overall rate of subclinical shedding was 9.8% with placebo, 11.9% with 5 mg of pritelivir daily, 7.4% with 25 mg daily, 1.6% with 75 mg daily, and 4.8% with 400 mg weekly (Figure 1C). The relative risks of subclinical shedding at pritelivir doses of 5 mg daily, 25 mg daily, 75 mg daily, and 400 mg weekly were 1.26 (95% CI, 0.67 to 2.35; P=0.48), 0.73 (95% CI, 0.37 to 1.47; P=0.38), 0.16 (95% CI, 0.05 to 0.49; P=0.001), and 0.47 (95% CI, 0.24 to 0.91; P=0.02), respectively.” (opens the source at this quote in a new tab) Copy Flag
Shedding by sex and tests of interaction Days with genital lesions by dose “Genital lesions were noted on 9.0% of days with placebo, 12.5% with 5 mg of pritelivir, 3.5% with 25 mg, 1.2% with 75 mg, and 1.2% with 400 mg (Figure 1D). The risk of genital lesions with pritelivir as compared with placebo was 1.39 (95% CI, 0.59 to 3.30; P=0.46) with 5 mg of pritelivir daily, 0.41 (95% CI, 0.16 to 1.09; P=0.07) with 25 mg daily, 0.13 (95% CI, 0.02 to 0.70; P=0.02) with 75 mg daily, and 0.13 (95% CI, 0.03 to 0.52; P=0.004) with 400 mg weekly.” (opens the source at this quote in a new tab) Copy Flag
Number of recurrences by dose Shedding and HSV DNA quantity on days with lesions Shedding, recurrence, and lesion rates with counts for the placebo and 75 mg daily arms Dose response as summarized by the investigators Concordance of participant-collected and investigator-collected swabs Viral resistance: sequencing of UL5 and UL52 reported in the publication Resistance sequencing substudy: samples sequenced in the resistance-associated regions “Of these, 823 swab specimens (median time of collection after treatment initiation, 22 days; range, 1–44 days), collected from 87 subjects (20 in the placebo group and 67 in one of the 4 dosage groups; Supplementary Table 4), contained an HSV-2 quantity of ≥5000 copies/mL and were subjected to resistance-region sequencing. Of the 823 samples, 688 (84%), from 80 patients, underwent successful sequencing of the UL5 gene, and 775 (94%), from 83 patients, underwent successful sequencing of the UL52 gene (Figure 2).” (opens the source at this quote in a new tab) Copy Flag
Resistance sequencing substudy: findings in the resistance-associated regions Resistance sequencing substudy: whole-gene sequencing of UL5 and UL52 Resistance sequencing substudy: conclusion Modeling study: dose response of shedding in the trial data Modeling study: simulated and observed shedding rates by arm Modeling study: estimated in vivo EC50 and inhibition of replication by dose Modeling study: predicted reduction in shedding at 150 mg daily Conclusion of the publication 3.1.3.8.4 Health-related quality of life and patient-reported outcomesNo evidence found.
Overall pattern of adverse events and the serious adverse event reported in the publication Discontinuations because of adverse events Safety conclusions of the investigators All-cause mortality, serious adverse events, and other adverse events by arm in the registry results Adverse events by system organ class and term in the registry results, participants affected of participants at risk Method of adverse event collection in the registry results FDA clinical hold after the trial and the nonclinical findings behind it
Summary AIC316-01-II-01 enrolled otherwise healthy, immunocompetent adults with genital HSV-2 infection, a population outside the labeled indication of immunocompromised adults with refractory mucocutaneous HSV infection. The regimens tested (5, 25, or 75 mg daily, or 400 mg weekly) differ from the approved regimen of 400 mg on day 1 followed by 100 mg daily. Treatment lasted 28 days, and 155 participants were analyzed in five arms of 29 to 33 participants. The primary endpoint was a virologic measure, and the investigators state that the trial was not powered to evaluate recurrences. The publication reports one serious adverse event (pancreatitis 2 weeks after treatment), and the registry results list none.
Limitations stated by the investigators Limitations of the resistance sequencing substudy Limitations of the modeling study Agreement on publication recorded in the registry
Objective stated in the publication Research question stated in the publication Purpose of comparing pritelivir with valacyclovir early in development Aim stated in the registry record 3.1.4.2 Location and study date
Sites and conduct period in the publication Dates of the FDA clinical hold and of study termination Study dates and status in the registry record Study locations in the registry record
Phase 2, randomized, double-blind, crossover design Randomization method and strata Masking with matching placebo and encapsulated valacyclovir Swab collection four times daily, symptom diary, and lesion-free start of each period HSV DNA assay, positivity threshold, and resistance monitoring Safety assessments and adverse event grading Rationale for the crossover design, its drawbacks, and the washout period Within-person comparison as described by the investigators' institution Design fields in the registry record Detailed description in the registry record Funding and role of the sponsor 3.1.4.4 Eligibility criteria
Inclusion criteria in the publication Exclusion criteria and dietary restrictions in the publication Inclusion criteria in the registry record Exclusion criteria in the registry record Age, sex, and healthy volunteer fields in the registry record
Pritelivir 100 mg daily after a 400 mg loading dose, and valacyclovir 500 mg daily Rationale for the pritelivir dose Treatment sequences in the registry record Measurement of adherence, and adherence to swabs and study drug Half-lives of acyclovir and pritelivir as stated by the investigators
3.1.4.6.1 Rationale for using within-participant genital HSV shedding as the primary endpoint
Primary endpoint defined in the publication Primary outcome measures in the registry record Advantages of shedding over recurrences as a trial outcome Proportion of the valacyclovir effect on lesions and recurrences explained by shedding Shedding as an indicator of transmission potential Secondary endpoints and definition of a shedding episode Endpoints as described in the company release 3.1.4.7 Statistical analysis description
3.1.4.7.1 Number of participants (Planned and analyzed)
Sample size calculation and planned enrollment Participants screened, randomized, and treated Participants in the primary and per-protocol analyses Participants contributing to efficacy analyses by first-period assignment Swabs collected during each treatment Participants enrolled, analyzed, and at risk in the registry results 3.1.4.7.2 Description of analysis sets
Intent-to-treat, per-protocol, and safety populations Statistical model, period and carryover tests, and significance level Full analysis set and safety reporting in the registry results
3.1.4.8.1 Participant disposition
Randomization and completion at study termination Participant randomized in error Screening outcomes in the registry results Participant flow by period and treatment sequence in the registry results Reasons for not completing by period and treatment sequence in the registry results Completion as described by the investigators' institution Sequence allocation and reduced participant number as printed in the company release 3.1.4.8.2 Baseline characteristics
Age, sex, race, time since acquisition, and recurrence frequency Demographic and clinical characteristics by first-period assignment in the publication Demographics by treatment sequence in the registry results 3.1.4.8.3 Efficacy results
Primary endpoint: genital HSV shedding during pritelivir and valacyclovir treatment Virologic end points by treatment in the publication Clinical end points by treatment in the publication Incidence rates per person-month and durations by treatment in the publication Quantity of HSV DNA in positive swabs Subclinical shedding and shedding on days with lesions Frequency and duration of shedding episodes Days with genital lesions and recurrences Period and carryover effects Subgroup analyses by sex, age, and duration of genital herpes Per-protocol and sensitivity analyses Resistance sequencing of swabs collected during pritelivir treatment Primary outcome measures in the registry results Statistical analysis of the within-subject shedding rate in the registry results Findings and conclusion stated in the publication Results as reported in the company release Shedding rate predicted by a mathematical model before comparison with the trial result 3.1.4.8.4 Health-related quality of life and patient-reported outcomes
Days with pain recorded by participants
Exposure and treatment-emergent adverse events overall Grade 3 and grade 4 events, deaths, and serious adverse events Participants with treatment-emergent adverse events by treatment in the publication, number (%) Discontinuations because of adverse events Skin and subcutaneous tissue disorders Laboratory findings: lymphocyte count and creatinine Nonclinical findings behind the FDA clinical hold, and corresponding events in trial participants FDA clinical hold and work to lift it partially, as described by the investigators' institution All-cause mortality, serious adverse events, and other adverse events in the registry results Adverse events by term in the registry results, participants affected of participants at risk Reporting threshold, time frame, and coding dictionary in the registry results Adverse events as reported in the company release
Summary AIC316-01-II-02 enrolled healthy, immunocompetent adults with 4 to 9 genital HSV-2 recurrences per year, a population outside the labeled indication of immunocompromised adults with refractory mucocutaneous HSV infection. The pritelivir regimen (400 mg on day 1, then 100 mg daily) matched the approved dose and was given for 28 days to suppress shedding. The sponsor terminated the trial after the FDA clinical hold of May 2013; 91 participants were randomized against 98 planned, and 56 completed both treatment periods. For the primary endpoint, the publication reports a relative risk of 0.42 (95% CI, 0.21 to 0.82) and the registry reports a risk ratio of 0.43 (95% CI, 0.30 to 0.63). The publication was corrected in January 2017.
Limitations stated by the investigators Need for longer-term efficacy and safety data Unresolved nonclinical safety findings as described by the lead investigator Correction to the published article Agreement on publication recorded in the registry
Objective of the trial of topical pritelivir 5% ointment in the protocol summary Registry description of the topical ointment trial 3.1.5.2 Location and study date
Planned sites and study period in the protocol summary Study dates and status in the registry record Study locations in the registry record
Topical pritelivir 5% ointment: randomized, double-blind, three-arm parallel-group design Participant-initiated topical treatment at the first sign of a recurrence Daily investigator assessment, diary, and follow-up after topical treatment Lesion stages assessed by the investigator Safety measurements and pharmacokinetic blood sampling “The following safety measures will be performed at screening and at Visit 5 (Day 5/6) and at the End of Trial Visit (Day 12±1) after initiation of treatment:” (opens the source at this quote in a new tab) Copy Flag
“Safety laboratory parameters, ie, serum chemistry, hematology, coagulation and urinalysis” (opens the source at this quote in a new tab) Copy Flag
“Vital signs, ie, systolic and diastolic blood pressure, pulse rate” (opens the source at this quote in a new tab) Copy Flag
“Standard 12-lead electrocardiogram (ECG) according to Einthoven, Goldberger and Wilson” (opens the source at this quote in a new tab) Copy Flag
“Blood sampling for pharmacokinetic analysis (one per day, in total seven samples) will be performed at randomization, daily at Visit 1 to Visit 5, and at the End of Trial Visit (Day 12±1). The time of PK blood sampling will be documented.” (opens the source at this quote in a new tab) Copy Flag
Design fields in the registry record Company statement on the start of the phase 2 trial of topical pritelivir 3.1.5.4 Eligibility criteria
Inclusion criteria for the topical ointment trial in the protocol summary Exclusion criteria for the topical ointment trial in the protocol summary “Known intolerance to pritelivir or any of the ointment ingredients (ie, butylated hydroxytoluene (BHT), PEG-400, PEG-4000, propylene glycol)” (opens the source at this quote in a new tab) Copy Flag
“Known intolerance to Zovirax® Cream or any of the ingredients (ie, acyclovir, cetostearyl alcohol, mineral oil, poloxamer 407, propylene glycol, sodium lauryl sulfate, and white petrolatum) or valacyclovir” (opens the source at this quote in a new tab) Copy Flag
“Any skin conditions that could interfere with the assessment of HL recurrences (eg, eczema, psoriasis, acne)” (opens the source at this quote in a new tab) Copy Flag
“Any other condition which in the opinion of the Investigator would interfere with successful completion of this clinical trial” (opens the source at this quote in a new tab) Copy Flag
“Pregnant and/or breastfeeding women” (opens the source at this quote in a new tab) Copy Flag
“Participation in any investigational drug trial within the last 30 days before randomization for this clinical trial” (opens the source at this quote in a new tab) Copy Flag
“Previous treatment with pritelivir tablets” (opens the source at this quote in a new tab) Copy Flag
“Previous participation in a HSV vaccination trial (unless having received placebo)” (opens the source at this quote in a new tab) Copy Flag
“Clinically relevant ECG abnormalities (eg, QTc according to Fridericia: QTcF > 450ms for males and QTcF > 470ms for females; PR > 220 ms) at screening” (opens the source at this quote in a new tab) Copy Flag
“Clinically relevant abnormalities in laboratory indices at screening which in the opinion of the investigator might have an impact on the safety and evaluability of the subject” (opens the source at this quote in a new tab) Copy Flag
“Known chronic infections which in the opinion of the investigator might have an impact on the safety and evaluability of the subject” (opens the source at this quote in a new tab) Copy Flag
“Evidence of active malignancy or immunodeficiency disease, or require chronic use of immunosuppressive drugs (eg, systemic steroids) or topical steroids, or chronically use antiviral medication with activity against HSV” (opens the source at this quote in a new tab) Copy Flag
“HIV positive based on screening labs.” (opens the source at this quote in a new tab) Copy Flag
Age, sex, and healthy volunteer fields in the registry record
Test product: topical pritelivir 5% w/w ointment Reference therapies: topical placebo ointment and Zovirax cream Topical treatment arms in the registry record Calculation of compliance with topical applications
3.1.5.6.1 Rationale for using the percentage of participants with non-ulcerative lesions as the primary endpoint
Primary endpoint of the topical ointment trial in the protocol summary Primary outcome measure and lesion stage scale in the registry record Assumed percentages of non-ulcerative lesions without treatment and with topical pritelivir Secondary efficacy endpoints: episode duration and lesion area Secondary efficacy endpoints: participant-assessed pain and tenderness Safety and pharmacokinetic endpoints “An overall summary of adverse events (AEs) will be provided including the number and percentage of subjects with any AE, treatment emergent AE (TEAE), related TEAE, serious AE, severe AE, and TEAE leading to early termination” (opens the source at this quote in a new tab) Copy Flag
“Safety signals such as hematological changes, lymphadenopathy, CRP increase, cutaneous adverse events and changes in (a)PTT” (opens the source at this quote in a new tab) Copy Flag
“Cmax, Tmax, AUC, if feasible” (opens the source at this quote in a new tab) Copy Flag
3.1.5.7 Statistical analysis description
3.1.5.7.1 Number of participants (Planned and analyzed)
Participants randomized and participants who treated a recurrence Participants started, analyzed for the primary outcome, and at risk for adverse events by topical treatment arm 3.1.5.7.2 Description of analysis sets
Intent-to-treat, per-protocol, and safety sets in the protocol summary Superiority test against placebo and descriptive comparison with the active comparator Analysis population and method for the primary outcome in the registry results
3.1.5.8.1 Participant disposition
Recruitment relative to the planned number of evaluable recurrences Participant flow among participants who started topical treatment 3.1.5.8.2 Baseline characteristics
Demographics of participants who started topical treatment, by arm 3.1.5.8.3 Efficacy results
Primary endpoint for topical pritelivir 5% ointment: percentage of participants with non-ulcerative recurrences Statistical comparison of topical pritelivir ointment with placebo ointment 3.1.5.8.4 Health-related quality of life and patient-reported outcomesNo evidence found.
All-cause mortality, serious adverse events, and other adverse events by topical treatment arm Adverse events by term for topical pritelivir ointment, placebo ointment, and Zovirax cream, participants affected of participants at risk Adverse event collection, time frame, and coding dictionary
Summary LipP1 tested pritelivir 5% w/w ointment applied 5 times daily for 4 days, a topical formulation other than the approved 100 mg tablet. It enrolled healthy adults with recurrent herpes labialis and excluded immunodeficiency disease and HIV infection, a population outside the labeled indication. Of 362 randomized participants, 223 treated a recurrence and 139 had no outbreak. Non-ulcerative recurrences occurred in 21.8% of participants receiving pritelivir ointment and 16.4% receiving placebo ointment (P = 0.4294). The comparison with Zovirax cream was planned as descriptive. The registry posts no results for secondary endpoints and records an agreement that restricts publication without the sponsor's consent.
Basis for the descriptive comparison of topical pritelivir with the active comparator Agreement on publication recorded in the registry 3.1.6 Expanded access and early access program case series
Purpose of the expanded access protocol Purpose of the early access program run with myTomorrows Purpose stated when the early access program was announced Hematopoietic cell transplant recipients with oral HSV-1 infection: aim of a 2-participant report Hematopoietic cell transplant recipients with genital HSV-2 infection: aim of a 2-participant report Stem cell transplant recipient with HSV-2 infection refractory to second-line therapy: aim of a case report Person living with HIV with orolabial HSV-2 infection: aim of a case report Stem cell transplant recipient given pritelivir for treatment and for secondary prophylaxis: aim of a case report Herpes simplex encephalitis, a use outside the labeled indication: aim of a case report Pediatric transplant recipients, a use outside the labeled indication: aim of an 8-participant series Hematopoietic cell transplant recipient treated in two episodes: aim of a case study within a review Hematopoietic cell transplant recipients with oral HSV-1 infection and HSV pneumonitis: aim of two cases within a pharmacology review 3.1.6.2 Location and study date
Expanded access record: country, protocol number, registration dates, and status Planned duration of the expanded access protocol Start of the early access program and number of countries Compassionate use program in Germany Data cut-off of the sponsor's aggregate early access data Person living with HIV in Canada: access route and treatment date Stem cell transplant recipient in the United Kingdom Pediatric transplant recipients: center and period Hematopoietic cell transplant recipient treated in two episodes: transplant dates
Expanded access protocol: design and monitoring Expanded access record: type and collaborator Early access program: request by the treating physician Early access program: individual review of each request Early access program as defined by the sponsor Reference to the expanded access program in a federal HIV guideline Hematopoietic cell transplant recipients with oral HSV-1 infection: two cases treated through the expanded access program Hematopoietic cell transplant recipients with genital HSV-2 infection: resistance genotyping Pediatric transplant recipients: retrospective case series with genotypic resistance testing Herpes simplex encephalitis: retrospective report of an individual treatment attempt Hematopoietic cell transplant recipient treated in two episodes: case selected for a review Review table of published expanded access cases in transplant recipients 3.1.6.4 Eligibility criteria
Expanded access protocol: population Expanded access protocol: main inclusion criteria Expanded access protocol: main exclusion criteria Early access program: eligible population as described by the sponsor Early access program: primary focus stated in a congress poster Early access program: population as described in a published case report Pediatric transplant recipients: inclusion in the case series
Expanded access protocol: pritelivir regimen Expanded access program: regimen and extension to 42 days as described in a published report Hematopoietic cell transplant recipients with genital HSV-2 infection: five pritelivir courses in 2 participants Hematopoietic cell transplant recipients with oral HSV-1 infection: regimen and duration in 2 participants Person living with HIV with orolabial HSV-2 infection: regimen Stem cell transplant recipient with esophagitis: administration through a gastrostomy tube, repeated courses, and secondary prophylaxis Herpes simplex encephalitis, a use outside the labeled indication: pritelivir by nasogastric tube with intravenous acyclovir Hematopoietic cell transplant recipient treated in two episodes: two 42-day courses Hematopoietic cell transplant recipients with oral HSV-1 infection and HSV pneumonitis: treatment in 2 participants Pediatric transplant recipients, a use outside the labeled indication: supply delay and limited duration Person living with HIV with anogenital HSV-2 infection: pritelivir among several therapies
3.1.6.6.1 Rationale for using lesion healing as an efficacy outcome
Assessments specified in the expanded access protocol Healing categories and handling of unknown outcomes in the sponsor's aggregate data Healing outcome in the earlier interim analysis of the early access program Hematopoietic cell transplant recipients with genital HSV-2 infection: resistance genotyping as an outcome Herpes simplex encephalitis: viral load in cerebrospinal fluid as an outcome 3.1.6.7 Statistical analysis description
3.1.6.7.1 Number of participants (Planned and analyzed)
Early access program: participants and countries in the earlier corporate slides Early access program: participants and evaluable treatment cycles in the later corporate slides Early access program: participants worldwide in a congress poster Hematopoietic cell transplant recipients with oral HSV-1 infection: 2 participants Hematopoietic cell transplant recipients with genital HSV-2 infection: 2 participants Pediatric transplant recipients: 3 pritelivir recipients among 8 participants Hematopoietic cell transplant recipients with oral HSV-1 infection and HSV pneumonitis: 2 participants 3.1.6.7.2 Description of analysis setsNo evidence found.
3.1.6.8.1 Participant disposition
Early access program: treatment cycles excluded from the sponsor's aggregate data Hematopoietic cell transplant recipients with oral HSV-1 infection: end of follow-up in 2 participants Hematopoietic cell transplant recipient with HSV pneumonitis: death during pritelivir treatment Herpes simplex encephalitis: discharge and death after treatment Hematopoietic cell transplant recipient treated in two episodes: death after the second episode Stem cell transplant recipient with HSV-2 infection: death as recorded in a review table 3.1.6.8.2 Baseline characteristics
Early access program: underlying conditions of treated participants Hematopoietic cell transplant recipients with oral HSV-1 infection: first of 2 participants Hematopoietic cell transplant recipients with oral HSV-1 infection: second of 2 participants Hematopoietic cell transplant recipients with oral HSV-1 infection: prior therapy as summarized in a commentary Hematopoietic cell transplant recipients with genital HSV-2 infection: first of 2 participants Hematopoietic cell transplant recipients with genital HSV-2 infection: second of 2 participants Stem cell transplant recipient with HSV-2 infection: characteristics as recorded in a review table Person living with HIV with orolabial HSV-2 infection: HIV status, prior therapy, and resistance “A 53-year-old male originally from Haiti was diagnosed with HIV in 2016 with initial viral load of 266,576 copies/mL and a CD4+ count of 3 × 106/L (0.4%) prompting treatment with abacavir, lamivudine, and dolutegravir.” (opens the source at this quote in a new tab) Copy Flag
“From 2018 to 2021, the patient developed numerous local recurrences. Multiple therapeutic regimens were trialed including topical foscarnet 1%, imiquimod 5% cream, topical cidofovir 1% cream, intravenous foscarnet, and intravenous cidofovir as summarized in Figure 1.” (opens the source at this quote in a new tab) Copy Flag
“In late 2021, the patient developed a large lesion on his right upper lip. His CD4+ count was stable at 238 cells/mm3 (12.4%) and his HIV viral load remained suppressed at <40 copies/mL. A swab of the lesion tested positive for HSV-2 by PCR. Subsequent genotypic resistance testing revealed a M183X nonsense mutation in UL23 encoding the viral thymidine kinase which leads to resistance to acyclovir and penciclovir” (opens the source at this quote in a new tab) Copy Flag
“The patient was again treated with IV cidofovir, but with limited improvement. Foscarnet was not prescribed to avoid the need for admission during the COVID-19 pandemic.” (opens the source at this quote in a new tab) Copy Flag
Stem cell transplant recipient with esophagitis: presentation, resistance, and prior therapy Herpes simplex encephalitis: participant and course before pritelivir “The patient was a 49-year-old man who received HCT for treatment-related acute myeloid leukemia after multiple myeloma therapies.” (opens the source at this quote in a new tab) Copy Flag
“On day +178, while still on valacyclovir prophylaxis, the patient presented to the allogeneic HCT outpatient clinic with fever, cognitive impairment, and general weakness.” (opens the source at this quote in a new tab) Copy Flag
“Resistance to acyclovir in the CSF could not be confirmed by UL23 genotyping, which identified polymorphisms C6G, G251C, P268T, Q89R, A192V, V267L, and D286E. We did not test for UL30 mutations in this case.” (opens the source at this quote in a new tab) Copy Flag
“Despite several days of intravenous acyclovir therapy and discontinuation of sedatives, the patient remained unresponsive even to painful stimuli.” (opens the source at this quote in a new tab) Copy Flag
“A subsequent cMRI showed ongoing progress with necrotic areas. As ultima ratio, the use of pritelivir was requested through the EAP.” (opens the source at this quote in a new tab) Copy Flag
Herpes simplex encephalitis: participant as described in the congress poster Pediatric transplant recipients: age, sex, and virus type in the 8-participant series Pediatric transplant recipients: characteristics of the 3 participants whose antiviral drugs included pritelivir Hematopoietic cell transplant recipient treated in two episodes: infection and prior therapy by episode Hematopoietic cell transplant recipient with oral HSV-1 infection: resistance and renal function before pritelivir Hematopoietic cell transplant recipient with HSV pneumonitis, a use outside the labeled indication: course before pritelivir Person living with HIV with anogenital HSV-2 infection: immune status and resistance 3.1.6.8.3 Efficacy results
Early access program: healing within 28 and 42 days in the sponsor's aggregate data Early access program: documented healing in an earlier interim analysis Early access program: severe manifestations noted in a congress poster Hematopoietic cell transplant recipients with oral HSV-1 infection: response in 2 participants Hematopoietic cell transplant recipients with oral HSV-1 infection: recurrence after pritelivir in 1 of 2 participants Hematopoietic cell transplant recipients with genital HSV-2 infection: healing and relapses in the first of 2 participants Hematopoietic cell transplant recipients with genital HSV-2 infection: healing and recurrences in the second of 2 participants Hematopoietic cell transplant recipients with genital HSV-2 infection: authors' account of relapse and resistance Stem cell transplant recipient with HSV-2 infection: symptomatic and virologic control Person living with HIV with orolabial HSV-2 infection: lesion response Stem cell transplant recipient with esophagitis: response, relapse, and resistance testing Stem cell transplant recipient with esophagitis: secondary prophylaxis and reintroduction Stem cell transplant recipient with esophagitis: case shown in the sponsor's corporate slides Herpes simplex encephalitis, a use outside the labeled indication: clinical, imaging, and virologic course Herpes simplex encephalitis, a use outside the labeled indication: pritelivir concentrations in plasma and cerebrospinal fluid Herpes simplex encephalitis, a use outside the labeled indication: summary in the congress poster Pediatric transplant recipients, a use outside the labeled indication: outcomes of the 3 participants whose antiviral drugs included pritelivir Hematopoietic cell transplant recipient treated in two episodes: outcome by episode Hematopoietic cell transplant recipients with oral HSV-1 infection and HSV pneumonitis: response in 2 participants Person living with HIV with anogenital HSV-2 infection: partial response 3.1.6.8.4 Health-related quality of life and patient-reported outcomes
Hematopoietic cell transplant recipients with oral HSV-1 infection: outpatient treatment and the participants' stated preference
Early access program: drug-related adverse events in the sponsor's aggregate data Hematopoietic cell transplant recipients with oral HSV-1 infection: tolerability in 2 participants Hematopoietic cell transplant recipients with genital HSV-2 infection: tolerability in 2 participants Stem cell transplant recipient with esophagitis: tolerability of prolonged courses Stem cell transplant recipient with esophagitis: authors' note on earlier long-term safety questions Herpes simplex encephalitis, a use outside the labeled indication: tolerability with intravenous acyclovir Hematopoietic cell transplant recipient treated in two episodes: tolerability Hematopoietic cell transplant recipients with oral HSV-1 infection and HSV pneumonitis: tolerability and one death during treatment Pediatric transplant recipients, a use outside the labeled indication: deaths among participants whose antiviral drugs included pritelivir Pediatric use: absence of safety data
Summary The expanded access record (NCT05844436) lists a status of Available and no location data. Aggregate early access outcomes come from sponsor slides alone: at the April 2024 data cut-off, 86 of 137 evaluable treatment cycles (63%) were healed or partially healed within 28 days, a category that combines complete and partial healing. Published reports are uncontrolled case reports and series with 1 to 3 pritelivir recipients each. Relapse after pritelivir was stopped is described in 3 reports. Use for encephalitis, pneumonitis, secondary prophylaxis, and children rests on 1 to 3 participants per use, and the encephalitis participant also received intravenous acyclovir. In the pediatric series, 1 of 3 pritelivir recipients had a good clinical response.
Sponsor aggregate data: excluded treatment cycles and preliminary status Hematopoietic cell transplant recipients with oral HSV-1 infection: authors' statements on the evidence and on secondary prophylaxis Commentary: open questions on severe disease and long-term prophylaxis Herpes simplex encephalitis: contribution of concurrent acyclovir and need for further data Herpes simplex encephalitis: sponsor employment of authors Pediatric transplant recipients: small numbers and access to treatment Review assessment of the early access evidence in transplant recipients Review assessment of the characterization of toxicity Case report on resistance monitoring during pritelivir treatment: removal by the publisher at the authors' request
Primary objective in the trial protocol Secondary objectives in the trial protocol Purpose of the thorough QT/QTc trial 3.1.7.2 Location and study date
Registry dates and status Protocol identifiers, version, and planned trial period Single-center conduct in a clinical pharmacology unit Protocol version 2 and comments from the United Kingdom regulator Protocol version used for the statistical analysis plan
Design summary in the registry record Overall design in the trial protocol Randomization ratio and schedule Blinding of participants, site staff, and sponsor “Subjects and all trial personnel, except for pharmacy staff at Richmond Pharmacology, and A&M for assignment of bioanalytical samples, will be blinded with respect to the assignment to group 1 (pritelivir) and 2 (matched placebo to pritelivir) as well as the treatment sequence of moxifloxacin and respective matching placebo in group 2.” (opens the source at this quote in a new tab) Copy Flag
“To maintain blinding, matching placebos (pritelivir or moxifloxacin, as appropriate) will be used at equivalent timepoints to verum treatment in other treatment sequences, so that all subjects receive the same number of tablets or capsules, with the same appearance, at equivalent timepoints in their respective treatment sequence.” (opens the source at this quote in a new tab) Copy Flag
“Over-encapsulated moxifloxacin- and matching placebo will be used to maintain double-blindness.” (opens the source at this quote in a new tab) Copy Flag
“The pharmacy staff preparing the IMP will not be blinded to trial drug assignment.” (opens the source at this quote in a new tab) Copy Flag
“Administrative and operational staff of the trial site, including Principal Investigator and trial manager as well as monitors, AiCuris staff and data managers will remain blinded during the course of the trial until Database Lock and finalization of the Statistical Analysis Plan.” (opens the source at this quote in a new tab) Copy Flag
Electrocardiogram recording days and Holter backup “12-lead ECG triplicates will be recorded from the bedside 12-lead-ECG on the Days -1, 1, 2, 6, 16, and 17 and will be analyzed afterwards in each group for these 6 days of documentation by a blinded reader.” (opens the source at this quote in a new tab) Copy Flag
“It is of note that Holter ECG data will be collected in parallel at screening to exclude anyone with pre-existing cardiac problems as well as on Days -1, 1, 2, 6, 16, and 17 as a back-up for the bedside 12-lead-ECGs.” (opens the source at this quote in a new tab) Copy Flag
“From 1 hour prior to dosing until 8 h (Day 2 and Day 17) or 24 h (Day -1, 1, Day 6 and Day 16) after dosing, a Holter-ECG will be carried out in all subjects.” (opens the source at this quote in a new tab) Copy Flag
Electrocardiogram acquisition and central reading Rationale for the design and the control groups FDA review of the proposed design Duration of participation Risk Benefit Committee and adaptive dose feature 3.1.7.4 Eligibility criteria
Age, sex, and healthy volunteer status in the registry record Inclusion criteria: health status and consent Inclusion criteria: body weight, tablet burden, and screening tests “Normal body weight as evidenced by a Body Mass Index (BMI) ≥18.0 and ≤25.0 kg/m2, and a body weight ≥50.0 kg at Screening.” (opens the source at this quote in a new tab) Copy Flag
“Subject had to be willing and able to swallow up to 4 tablets (pritelivir or matching placebo) and 1 capsule (over-encapsulated moxifloxacin or matching placebo) at least twice during the trial.” (opens the source at this quote in a new tab) Copy Flag
“Subjects must have a negative test result for HIV-I- and -II-antibody, HBsAg, anti-hepatitis B core antigen (HBc) (IgG + IgM) and anti-hepatitis C virus (HCV) at Screening.” (opens the source at this quote in a new tab) Copy Flag
“Subjects had to have negative urine tests for drugs of abuse (benzodiazepines, opiates, amphetamines, methadone, cocaine, cannabinoids, barbiturates, cotinine) and negative breath alcohol tests at Screening and Admission for the in-house phase (Day -2).” (opens the source at this quote in a new tab) Copy Flag
“In women, negative serum β-HCG (beta-human chorionic gonadotropin) test at Screening and negative urine β-HCG test on Day -2.” (opens the source at this quote in a new tab) Copy Flag
“Subject agreed to pharmacogenomic blood sampling.” (opens the source at this quote in a new tab) Copy Flag
Inclusion criteria: electrocardiographic requirements Inclusion criteria: contraception Exclusion criteria: cardiac history, vital signs, and electrocardiographic intervals Exclusion criteria: medical history “History or current evidence of clinically relevant allergies or idiosyncrasy to drugs or food.” (opens the source at this quote in a new tab) Copy Flag
“History of any moderate or severe allergy or any known allergy to any active or inactive ingredient(s) of moxifloxacin investigational medicinal product (IMP), pritelivir IMP, or their respective matching placebos.” (opens the source at this quote in a new tab) Copy Flag
“History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematologic, endocrine, metabolic, neurological, psychiatric, or other disease suspected to influence pharmacokinetics or safety of the IMP.” (opens the source at this quote in a new tab) Copy Flag
“History or any current evidence of a dermatological condition requiring treatment by a general practitioner (GP) or specialist (with the exception of burns, fungal infections, and/or warts).” (opens the source at this quote in a new tab) Copy Flag
“History of malignancy.” (opens the source at this quote in a new tab) Copy Flag
“Chronic or clinically relevant acute infections or febrile illness within 5 days prior to administration of the IMP.” (opens the source at this quote in a new tab) Copy Flag
“Diseases or surgery of the gastrointestinal tract which could have interfered with drug absorption (note: this is not applicable for minor abdominal surgery such as eg, appendectomy and herniotomy).” (opens the source at this quote in a new tab) Copy Flag
“Subject was lactating or breastfeeding.” (opens the source at this quote in a new tab) Copy Flag
Exclusion criteria: laboratory values Exclusion criteria: medications, vaccination, and investigational drugs Exclusion criteria: alcohol, tobacco, and substance use Exclusion criteria: diet, communication, and vulnerable persons Withdrawal criteria in the trial protocol
Regimens by group in the registry record Pritelivir and pritelivir placebo dosing Moxifloxacin and moxifloxacin placebo dosing Tablets and capsules dispensed for each dose Administration with water and fasting on electrocardiogram days Selection of the therapeutic dose and the loading dose Selection of the supratherapeutic dose Selection of the moxifloxacin dose Dose reduction rules for the supratherapeutic dosing period
3.1.7.6.1 Rationale for using placebo-corrected change in QTcF as the primary endpoint
Primary endpoint defined in the statistical analysis plan Primary outcome measure in the registry record Threshold of regulatory concern for the change in QTcF Regulatory guidance behind the endpoint and the Fridericia correction Planned replacement of QTcF by an individual correction after a heart rate effect Role of moxifloxacin as the positive control Nonclinical and earlier clinical electrocardiographic findings cited in the trial protocol Secondary electrocardiographic variables Categorical analyses of QTcF Categorical analyses of PR interval, QRS duration, and heart rate Pharmacokinetic sampling and plasma concentration endpoints Blood sampling times for pritelivir and its metabolites “Day 1: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 h post-dose” (opens the source at this quote in a new tab) Copy Flag
“Day 3 to 5: pre-dose (trough),” (opens the source at this quote in a new tab) Copy Flag
“Day 6: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 h post-dose” (opens the source at this quote in a new tab) Copy Flag
“Day 13 to 15: pre-dose (trough),” (opens the source at this quote in a new tab) Copy Flag
“Day 16: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 h post-dose” (opens the source at this quote in a new tab) Copy Flag
Reference ranges for electrocardiographic parameters Safety and tolerability endpoints 3.1.7.7 Statistical analysis description
3.1.7.7.1 Number of participants (Planned and analyzed)
Planned number of participants Reserve participants at screening Participants enrolled and included in the baseline analysis Participants analyzed for the primary outcome measure 3.1.7.7.2 Description of analysis sets
Safety set and pharmacokinetic set Analysis set for the concentration-QTc analysis Maximum time between blood sampling and electrocardiogram for a paired measurement Analysis populations posted with the registry results Baseline for electrocardiographic variables Concentration-QTc models for the primary analysis Assay sensitivity analysis Time course analysis of electrocardiographic variables Safety analysis, pharmacokinetic analysis, and interim analysis
3.1.7.8.1 Participant disposition
3.1.7.8.2 Baseline characteristics
Sex and ethnicity, count and percentage of participants Race, count and percentage of participants 3.1.7.8.3 Efficacy results
Cardiac electrophysiology statement in the prescribing information Statistical analysis of the primary outcome measure posted on the registry Mean QTcF in milliseconds by group and time point 3.1.7.8.4 Health-related quality of life and patient-reported outcomesNot applicable.
Adverse event reporting period and group definitions Deaths, serious adverse events, and other adverse events Adverse events by system organ class and preferred term
Summary AIC316-03-I-07 enrolled 64 healthy adults aged 18 to 45 years at 1 site; concomitant medication was an exclusion criterion, with exceptions for hormonal contraception, hormone replacement therapy, and a single intake judged to have no clinical relevance. The highest pritelivir dose was 400 mg once daily, given for 10 days. The registry posts mean QTcF by time point and one model-based prediction with its 90% confidence interval. It posts no moxifloxacin assay sensitivity result, no heart rate, PR interval, or QRS duration result, and no pharmacokinetic result. No journal publication of the trial was identified.
FDA comment on the adequacy of dose selection Hepatic and renal impairment trials in progress when the protocol was written Agreement restricting investigator publication
Objectives in the protocol and statistical plan summary Objective in the registry record 3.1.8.2 Location and study date
Registry dates and status Trial center, planned trial period, and document dates
Design as conducted, in the registry record Design as planned, in the protocol and statistical plan summary Pharmacokinetic sampling period Clinic stay through day 5 of each period, as stated in a dietary restriction 3.1.8.4 Eligibility criteria
Age, sex, and healthy volunteer status in the registry record Main criteria for inclusion in the protocol and statistical plan summary Inclusion criteria: health status, consent, and body weight Inclusion criteria: contraception and pregnancy testing Inclusion criteria: infection and drug screening “Subjects had to have a negative test result for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), and human immunodeficiency virus (HIV) at Screening;” (opens the source at this quote in a new tab) Copy Flag
“Subjects had to have negative urine tests for drugs of abuse (metamphetamines, amphetamines, 3,4-Methylendioxyamphetamin (MDMA), barbiturates, benzodiazepines, cannabinoids, opioids, cocaine and tricyclic antidepressants) and negative breath alcohol tests at Screening and Admission in each Treatment Period.” (opens the source at this quote in a new tab) Copy Flag
Exclusion criteria: medical history “History or current evidence of clinically relevant allergies or idiosyncrasy to drugs or food” (opens the source at this quote in a new tab) Copy Flag
“History of allergic reactions to any active or inactive ingredient(s) of the trial medication(s)” (opens the source at this quote in a new tab) Copy Flag
“History or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other disease suspected to influence pharmacokinetics or safety of PTV” (opens the source at this quote in a new tab) Copy Flag
“History of malignancy” (opens the source at this quote in a new tab) Copy Flag
“Febrile or infectious illness within 5 days prior to administration of Investigational Medicinal Product” (opens the source at this quote in a new tab) Copy Flag
“Chronic or clinically relevant acute infections” (opens the source at this quote in a new tab) Copy Flag
“Diseases or surgery of the gastrointestinal tract which may have interfered with drug absorption (note: this was not applicable for minor abdominal surgery such as eg, appendectomy and herniotomy)” (opens the source at this quote in a new tab) Copy Flag
“Subject was lactating or breastfeeding” (opens the source at this quote in a new tab) Copy Flag
Exclusion criteria: vital signs, electrocardiogram, and laboratory values Exclusion criteria: medications, investigational products, and blood donation Exclusion criteria: diet, alcohol, and tobacco “Consumption of any (eg, CYP1A2, CYP3A4) enzyme inducing or inhibiting aliments and beverages (eg, but not limited to broccoli, Brussels sprout, grapefruit, grapefruit juice, Seville orange, star fruit, tonic water, bitter lemon etc.) within 2 weeks prior to the Screening (Pre-trial examination)” (opens the source at this quote in a new tab) Copy Flag
“Consumption of alcohol and tobacco products within 48 hours prior to admission to the clinic until discharge of each period” (opens the source at this quote in a new tab) Copy Flag
“Vegetarian diet or other dietary habits which would have precluded the subject's acceptance of standardized meals” (opens the source at this quote in a new tab) Copy Flag
“Smoking of more than 10 cigarettes/cigars/pipes per Day and/or inability to refrain from smoking during confinement” (opens the source at this quote in a new tab) Copy Flag
“Intake of more than 12 units of alcohol per week (one unit of alcohol equals approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits)” (opens the source at this quote in a new tab) Copy Flag
Treatment periods in the registry record Products, doses, and duration in the protocol and statistical plan summary Regimen as described in the prescribing information
3.1.8.6.1 Rationale for using pritelivir exposure as the primary endpoint
Primary pharmacokinetic variables Primary outcome measures in the registry record Clinical relevance of reduced pritelivir exposure in the prescribing information Secondary pharmacokinetic variables Secondary outcome measures in the registry record 3.1.8.7 Statistical analysis description
3.1.8.7.1 Number of participants (Planned and analyzed)
Planned number of participants Participants enrolled and analyzed on the registry Participants in the pharmacokinetic comparison reported in the prescribing information 3.1.8.7.2 Description of analysis sets
Pharmacokinetic set and safety set Analysis of relative bioavailability Descriptive statistics for pharmacokinetic data Safety analysis and electrocardiogram analysis Baseline analysis population posted with the registry results
3.1.8.8.1 Participant disposition
Enrollment and completion by treatment period Participant flow for the overall study 3.1.8.8.2 Baseline characteristics
Race, count and percentage of participants 3.1.8.8.3 Efficacy results
Geometric mean ratios of pritelivir exposure with and without esomeprazole Percentage decrease in pritelivir exposure with esomeprazole Primary outcome measures on the registry: maximum concentration and area under the curve Secondary outcome measures on the registry: time to maximum concentration and lag time Secondary outcome measures on the registry: elimination, clearance, and volume of distribution Prescribing information warning on acid-reducing agents Prescribing information instructions for proton pump inhibitors Other acid-reducing agents evaluated in the phase 3 trial, as stated in the prescribing information 3.1.8.8.4 Health-related quality of life and patient-reported outcomesNot applicable.
Adverse event reporting period Deaths, serious adverse events, and other adverse events Adverse events by system organ class and preferred term
Summary AIC316-03-I-01 was an open-label, fixed-sequence trial without randomization in 16 healthy adults aged 18 to 45 years at 1 site. Pritelivir was given as a single 100 mg dose under fasted conditions, and esomeprazole 40 mg once daily was the only acid-reducing regimen tested. One participant withdrew before the second period, and 15 participants entered it. The registry posts means and standard deviations; the geometric mean ratios appear in the prescribing information. No metabolite result is posted, and no journal publication of the trial was identified.
Agreement restricting investigator publication 3.1.9 AIC316-03-I-03 and AIC316-03-I-06
In vitro findings that prompted the clinical interaction trials Perpetrator mechanisms evaluated in both trials Trial AIC316-03-I-03: substrates of CYP2C9, CYP2B6, CYP3A4, and OATP2B1 Trial AIC316-03-I-06: substrates of CYP2C8 and BCRP Expectation for pritelivir as a substrate of CYP enzymes and efflux transporters 3.1.9.2 Location and study date
Trial AIC316-03-I-03: trial site and ethics committee Trial AIC316-03-I-06: trial site and ethics committee Conduct standards and consent in both trials
Trial AIC316-03-I-03: sequential, single-center, open-label phase 1 design Trial AIC316-03-I-03: screening, confinement, and end-of-trial visit Trial AIC316-03-I-03: pharmacokinetic sampling schedule “Serial blood samples (3 mL at each time point) for determination of celiprolol in plasma were taken on days 1 and 8 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 36 hours postdose.” (opens the source at this quote in a new tab) Copy Flag
“Serial blood samples (3 mL at each time point) for determination of flurbiprofen, 4-hydroxy-flurbiprofen (OH-flurbiprofen), bupropion, 4-hydroxy-bupropion (OH-bupropion), and midazolam in plasma were taken on days 3 and 19 at predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 72 hours postdose.” (opens the source at this quote in a new tab) Copy Flag
“Predose blood samples (3 mL at each time point) for determination of pritelivir in plasma and its metabolites PPA and ATS were taken predose on days 8, 9, 17, 18, 19, and 20.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-06: sequential, single-center, open-label phase 1 design Trial AIC316-03-I-06: repaglinide given with the loading dose and again at steady state Trial AIC316-03-I-06: screening, confinement, and end-of-trial visit Trial AIC316-03-I-06: pharmacokinetic sampling schedule “Serial blood samples (3 mL at each time point) for determination of repaglinide in plasma were taken on days 1, 7, and 20 at predose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours postdose.” (opens the source at this quote in a new tab) Copy Flag
“Serial blood samples (3 mL at each time point) for determination of rosuvastatin in plasma were taken on days 2 and 9 at predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours postdose.” (opens the source at this quote in a new tab) Copy Flag
“Predose blood samples (3.4 mL at each time point) for determination of pritelivir in plasma and its metabolites PPA and ATS were taken predose on days 9, 10, 17, 18, 19, and 20.” (opens the source at this quote in a new tab) Copy Flag
Substrates given under steady-state pritelivir at the therapeutic dose Bioanalytical methods and lower limits of quantification for pritelivir and its metabolites Bioanalytical methods for the probe substrates 3.1.9.4 Eligibility criteria
Inclusion criteria in both trials: healthy adults aged 18 to 55 years Exclusion criteria in both trials: disease history and abnormal findings “Subjects with a history or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other disease or malignancy were excluded.” (opens the source at this quote in a new tab) Copy Flag
“Subjects were also excluded in case of any clinically relevant abnormalities in ECG, vital signs, clinical chemical, hematological, or any other laboratory values.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-03: exclusion of CYP2C9 poor metabolizers Prior and concomitant medication restrictions in both trials Diet, smoking, and alcohol restrictions in both trials
Trial AIC316-03-I-03: probe substrate doses and dosing days Trial AIC316-03-I-03: pritelivir regimen and administration conditions Trial AIC316-03-I-06: probe substrate doses and dosing days Trial AIC316-03-I-06: pritelivir regimen and administration conditions “A loading dose of 400 mg of pritelivir was administered on day 7, followed by once-daily administrations of 100 mg of pritelivir from day 8 to day 20, inclusive.” (opens the source at this quote in a new tab) Copy Flag
“Pritelivir was administered orally after an overnight fast, 1 hour before breakfast or 2 hours after breakfast, with 240 mL of water.” (opens the source at this quote in a new tab) Copy Flag
“On PK sampling days (days 1, 2, 7, 9, 18, and 20), subjects received the first meal 4 hours after dosing.” (opens the source at this quote in a new tab) Copy Flag
“Repaglinide and rosuvastatin were administered after an overnight fast, with 240 mL of water, and subjects received the first meal 4 hours after dosing.” (opens the source at this quote in a new tab) Copy Flag
“Pritelivir was administered orally 1 hour before breakfast or 2 hours after breakfast, except for day 18 on which subjects were fasted overnight until 4 hours after dosing.” (opens the source at this quote in a new tab) Copy Flag
Pritelivir trough concentrations confirming steady state in both trials “Mean predose (Ctrough) plasma concentrations of pritelivir, PPA, and ATS were constant over time for both trials, confirming the attainment of steady state.” (opens the source at this quote in a new tab) Copy Flag
“Pritelivir trough concentrations (days 8, 9 and 17, 18, 19 and 20 for Trial 03 and days 9, 10, 17, 18, 19, and 20 for Trial 06) confirmed that the interaction of pritelivir with drug transporters and CYP substrates was evaluated under steady-state conditions within the therapeutic range.” (opens the source at this quote in a new tab) Copy Flag
3.1.9.6.1 Rationale for using probe substrate exposure ratios (Cmax and AUC) as the primary pharmacokinetic endpoint
Exposure comparison with and without pritelivir Pharmacokinetic parameters calculated in both trials “For both trials PK analyses were performed with standard noncompartmental methods using the validated computer program Phoenix® WinNonlin® (version 8.1.1; Certara LP).” (opens the source at this quote in a new tab) Copy Flag
“The following PK parameters were calculated for celiprolol, flurbiprofen, OH-flurbiprofen, bupropion and OH-bupropion, midazolam, repaglinide, and rosuvastatin: Cmax, tmax, AUC0-last, AUC0-inf, t1/2z, and CLss/F (not for OH-flurbiprofen and OH-bupropion).” (opens the source at this quote in a new tab) Copy Flag
“In addition, for OH-flurbirofen and OH-bupropion the m/p ratios of AUC0-last (ratio AUC0-last,m/p) and AUC0-inf (ratio AUC0-inf,m/p) were calculated.” (opens the source at this quote in a new tab) Copy Flag
“For pritelivir, PPA and ATS in plasma, Ctrough was calculated.” (opens the source at this quote in a new tab) Copy Flag
No-effect boundary of 80% to 125% for the 90% confidence interval Trial AIC316-03-I-03: selection of the Geneva cocktail substrates Trial AIC316-03-I-03: selection of celiprolol as the OATP2B1 substrate Trial AIC316-03-I-06: selection of repaglinide and rosuvastatin Hydroxy metabolites measured as markers of CYP2C9 and CYP2B6 activity Safety and tolerability assessments in both trials 3.1.9.7 Statistical analysis description
3.1.9.7.1 Number of participants (Planned and analyzed)
Trial AIC316-03-I-03: planned sample size Trial AIC316-03-I-03: participants enrolled and analyzed Trial AIC316-03-I-06: planned sample size Trial AIC316-03-I-06: participants enrolled and analyzed Powering of the trials for an interaction of 20% to 25% Participants contributing to each descriptive pharmacokinetic parameter 3.1.9.7.2 Description of analysis sets
Safety and pharmacokinetic population in both trials Trial AIC316-03-I-03: linear mixed-effects model Trial AIC316-03-I-06: linear mixed-effects model Test and reference treatments for the least square means ratios Trial AIC316-03-I-03: sensitivity analysis of celiprolol excluding one participant Descriptive statistics and handling of concentrations below the limit of quantification Rules for excluding a parameter from descriptive statistics Safety analysis by descriptive statistics
3.1.9.8.1 Participant disposition
Trial AIC316-03-I-03: all 16 participants completed Trial AIC316-03-I-06: all 16 participants completed 3.1.9.8.2 Baseline characteristics
Trial AIC316-03-I-03: sex, age, body weight, and body mass index Trial AIC316-03-I-03: CYP2C9 genotype Trial AIC316-03-I-06: sex, age, body weight, and body mass index 3.1.9.8.3 Efficacy results
Trial AIC316-03-I-03: least square means ratios for OATP2B1, CYP3A4, CYP2C9, and CYP2B6 substrates Trial AIC316-03-I-06: least square means ratios for CYP2C8 and BCRP substrates Trial AIC316-03-I-03: celiprolol and the OATP2B1 interaction “The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf after administration of celiprolol with pritelivir (day 8, test) compared with celiprolol alone (day 1, reference), exceeded 100% (range 111.9%-113.3%, excluding subject 107) and the upper bound of the 90% CIs exceeding the 125% no-effect boundary.” (opens the source at this quote in a new tab) Copy Flag
“Furthermore, no inhibition of the intestinal uptake transporter OATP2B1 was observed.” (opens the source at this quote in a new tab) Copy Flag
“In the case of inhibition of OATP2B1 by pritelivir, a LSmeans ratio below 100% was expected.” (opens the source at this quote in a new tab) Copy Flag
“However, celiprolol LSmeans ratios for Cmax, AUC0-last, and AUC0-inf were slightly increased after administration with pritelivir under steady-state conditions, with the upper bounds of the ratios exceeding the 125% no-effect boundary.” (opens the source at this quote in a new tab) Copy Flag
“As the results of the in vitro studies did not predict a potentially clinically relevant effect on the OATP2B1 hepatic uptake transporter, it is not likely that this caused the slight increase.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-03: celiprolol exposure in the excluded participant Trial AIC316-03-I-03: midazolam and the CYP3A4 interaction Trial AIC316-03-I-03: flurbiprofen, OH-flurbiprofen, and the CYP2C9 interaction Trial AIC316-03-I-03: bupropion, OH-bupropion, and the CYP2B6 interaction Trial AIC316-03-I-06: repaglinide with the 400 mg loading dose (CYP2C8 inhibition) Trial AIC316-03-I-06: repaglinide at pritelivir steady state (net CYP2C8 inhibition and induction) “The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf (n = 3) of repaglinide were slightly increased (range 113.2-127.5) after administration of multiple doses of pritelivir (400 mg on day 7 followed by 100 mg once daily (qd) from days 8 to 20; day 20, test) compared with repaglinide alone (day 1, reference).” (opens the source at this quote in a new tab) Copy Flag
“The upper bounds of the 90% CIs all exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab) Copy Flag
“When combined with 100 mg pritelivir at steady state, there was no net induction of CYP2C8 activity, but as the upper bound of the 90% CIs exceeded the 125% no-effect boundary, a weak net inhibition of CYP2C8 cannot be excluded.” (opens the source at this quote in a new tab) Copy Flag
“However, as the LSmeans ratio for Cmax was far below 125% (113.2%) and the LSmeans ratio for AUC0-last was just above 125% (127.5%), this is likely not of clinical relevance.” (opens the source at this quote in a new tab) Copy Flag
“Thus, the combined results of the effects of single and multiple doses of pritelivir on the pharmacokinetics of the CYP2C8 substrate repaglinide indicate that pritelivir does not have a clinically relevant effect on CYP2C8.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-06: rosuvastatin and the BCRP interaction “The LSmeans ratios of Cmax, AUC0-last, and AUC0-inf (n = 8) after administration of rosuvastatin with pritelivir (day 9, test) compared with rosuvastatin alone (day 2, reference) exceeded 100% (136.9% and 167.0% for AUC0-last and Cmax, respectively) and the lower and upper bounds of the 90% CIs both exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab) Copy Flag
“Consistent with the in vitro results, a therapeutic 100-mg multiple once-daily regimen of pritelivir showed a weak inhibitory potential on the intestinal efflux transporter BCRP (<2-fold).” (opens the source at this quote in a new tab) Copy Flag
“When combined with 400 mg of pritelivir on day 7 followed by 100 mg once daily on day 9, the LSmeans ratios for Cmax, AUC0-last, and AUC0-inf of rosuvastatin were increased (167.0, 141.3, and 136.9, respectively) and the lower bound of the CI exceeded the 125% no-effect boundary.” (opens the source at this quote in a new tab) Copy Flag
“Although there is no standard classification for the effects of transporter inhibitors, the increase in rosuvastatin is analogous to weak inhibition in the scenario of CYP inhibition with a sensitive substrate” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-03: descriptive pharmacokinetic parameters of the parent substrates Trial AIC316-03-I-03: descriptive pharmacokinetic parameters of the hydroxy metabolites Trial AIC316-03-I-06: descriptive pharmacokinetic parameters of repaglinide and rosuvastatin Statistics shown in the descriptive parameter tables Pritelivir exposure by sex at steady state in both trials Authors' conclusions for CYP3A4, CYP2C9, and CYP2B6 Authors' overall conclusion on the interaction potential of pritelivir Prescribing information: rosuvastatin exposure with pritelivir Prescribing information: BCRP substrate interaction statement Prescribing information: CYP2B6, CYP2C8, CYP2C9, CYP3A4, and OATP2B1 substrates 3.1.9.8.4 Health-related quality of life and patient-reported outcomesNot applicable.
Comparability of adverse event counts between treatments Trial AIC316-03-I-03: treatment-emergent adverse events Trial AIC316-03-I-03: adverse events considered related to trial medication Trial AIC316-03-I-03: vital signs, electrocardiograms, and laboratory parameters Trial AIC316-03-I-06: treatment-emergent adverse events Trial AIC316-03-I-06: moderate-intensity events and events considered related Authors' conclusion on safety and tolerability in both trials
Summary Both trials were single-center, open-label, sequential phase 1 trials, each enrolling 16 healthy participants (age range 22 to 55 years in Trial 03 and 25 to 55 years in Trial 06). Each was sized to characterize an interaction of 20% or 25%, and the authors state the trials were not powered to show the absence of an effect. AUC0-inf ratios were based on 3 of 16 participants for repaglinide and 8 of 16 for rosuvastatin. Celiprolol is also a P-glycoprotein substrate and rosuvastatin is also an OATP2B1 substrate. Treatment days differed between treatments, which limits comparison of adverse event counts. The sponsor funded both trials, and 5 authors are its employees.
Trials powered to characterize an interaction and to interpret it against no-effect boundaries Trial AIC316-03-I-03: celiprolol as a non-specific OATP2B1 substrate Trial AIC316-03-I-06: rosuvastatin as a substrate of both BCRP and OATP2B1 Trial AIC316-03-I-06: weak net inhibition of CYP2C8 at steady state Absence of a standard classification for transporter inhibition Unequal treatment days in the adverse event comparison Funding and author affiliations 3.1.10 AIC316-03-I-04 and AIC316-03-I-05
Effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites Elimination pathways and protein binding as the reasons for both trials Intended population of pritelivir 3.1.10.2 Location and study date
Trial site of AIC316-03-I-04 and AIC316-03-I-05 Regulatory and ethics approval in both trials
Trial AIC316-03-I-04: single-center, open-label phase 1 design in four renal function groups Trial AIC316-03-I-04: matching of the control group on age and body mass index Trial AIC316-03-I-05: single-center, open-label phase 1 design in moderate hepatic impairment Screening, confinement, and follow-up in both trials Pharmacokinetic sampling schedule in both trials “Serial blood samples for PK analysis of pritelivir and metabolites PPA, ATS, and PPA-acyl glucuronide in plasma and blood (3 mL at each time point per matrix) were collected before dosing on Day 1 and after dosing at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, 216, 288, and 360 hours.” (opens the source at this quote in a new tab) Copy Flag
Single-dose design and its justification Trial AIC316-03-I-05: restriction to moderate hepatic impairment Matched control groups in both trials Bioanalytical methods and lower limits of quantification “All analyses were undertaken using fully validated procedures.” (opens the source at this quote in a new tab) Copy Flag
“Plasma concentrations of pritelivir, PPA, ATS, and PPA-acyl glucuronide were determined using a validated mass spectrometry, high-performance liquid chromatography (HPLC)–tandem mass spectrometry method by A&M Labor für Analytik und Metabolismusforschung Service GmbH (Bergheim, Germany).” (opens the source at this quote in a new tab) Copy Flag
“The lower limit of quantification (LLOQ) for pritelivir, PPA, ATS, and PPA-acyl glucuronide in plasma was 10.0, 2.00, 2.00, and 0.100 ng/mL, respectively.” (opens the source at this quote in a new tab) Copy Flag
Determination of unbound pritelivir by rapid equilibrium dialysis 3.1.10.4 Eligibility criteria
Control groups in both trials: age, body mass index, and body weight Trial AIC316-03-I-04: estimated glomerular filtration rate by group Trial AIC316-03-I-04: definition of stable renal impairment Trial AIC316-03-I-05: Child-Pugh stage B Stable health status and exclusion criteria in both trials “Subjects had no clinically relevant unstable disease as assessed by the investigator, and renally impaired subjects had stable renal impairment based on a screening examination including medical history, physical examination, blood pressure, pulse rate, electrocardiogram (ECG) assessment, and clinical laboratory results.” (opens the source at this quote in a new tab) Copy Flag
“Subjects with a history or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic (Trial 04), renal (Trial 05), gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other disease or malignancy were excluded.” (opens the source at this quote in a new tab) Copy Flag
“Subjects were also excluded in case of any clinically relevant abnormalities in ECG; vital signs; or clinical chemical, hematological, or any other laboratory values.” (opens the source at this quote in a new tab) Copy Flag
Prior medication, diet, smoking, and alcohol restrictions in both trials
Single oral dose of pritelivir 100 mg under fasted conditions in both trials Concomitant medication permitted for control participants Concomitant medication permitted for participants with renal or hepatic impairment “For impaired subjects, concomitant medications were not allowed throughout the trial, other than stable doses of medically required medication (including over-the-counter medication), except for paracetamol (not exceeding 2 g/day or ibuprofen not exceeding 1200 mg per day [hepatically impaired subjects only]), topical dermatological products, hormonal contraceptives, hormone replacement therapy, proton pump inhibitors (had to be stopped from 3 days prior to dosing until after the 24 hours postdose PK sampling), H2 blockers (had to be stopped from 2 days prior to dosing until after the 24 hours postdose PK sampling), and other concomitant medication, including antacids and phosphate-binding drugs if taken at least 2 hours before or 4 hours after pritelivir administration.” (opens the source at this quote in a new tab) Copy Flag
Interruption of proton pump inhibitors around the pritelivir dose
3.1.10.6.1 Rationale for using pritelivir AUC0-inf, AUC0-last, and cmax as the primary pharmacokinetic variables
Primary and secondary pharmacokinetic variables in both trials “To evaluate the effect of mild, moderate, and severe renal impairment (Trial 04) and moderate hepatic impairment (Trial 05) on the PK of pritelivir and its metabolites (PPA, ATS, and PPA-acyl glucuronide), a linear mixed-effects model was applied on the log-transformed parameters AUC0-inf, AUC0-last, and Cmax (primary variables for pritelivir and secondary variables for its metabolites) and AUC0-inf,u, AUC0-last,u, and Cmax,u (secondary variables, pritelivir only) with group as fixed effect.” (opens the source at this quote in a new tab) Copy Flag
Pharmacokinetic parameters calculated “For both trials, PK analyses were performed with standard noncompartmental methods using the validated computer program Phoenix WinNonlin (version 8.1.1; Certara LP, USA).” (opens the source at this quote in a new tab) Copy Flag
“For pritelivir, PPA, ATS, and PPA–acyl glucuronide: maximum plasma concentration (Cmax), time to maximum concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC0-last), AUC from time 0 to infinity (AUC0-inf), terminal elimination half-life (t1/2z), apparent clearance (CL/F; pritelivir only), and fraction unbound (fu; pritelivir only).” (opens the source at this quote in a new tab) Copy Flag
“For pritelivir, the unbound parameters Cmax,u, AUC0-last,u, AUC0-inf,u, and CLu/F.” (opens the source at this quote in a new tab) Copy Flag
“For the metabolites, PPA, ATS, and PPA-acyl glucuronide metabolite-to-parent ratios were calculated for AUC0-last and AUC0-inf (AUC0-last,m/p and AUC0-inf,m/p).” (opens the source at this quote in a new tab) Copy Flag
Unbound exposure measured because impairment can change protein binding Metabolites measured on the basis of urinary excretion Safety and tolerability assessments in both trials 3.1.10.7 Statistical analysis description
3.1.10.7.1 Number of participants (Planned and analyzed)
Trial AIC316-03-I-04: participants planned by group Trial AIC316-03-I-04: participants enrolled and analyzed Trial AIC316-03-I-05: participants planned by group Trial AIC316-03-I-05: participants enrolled and analyzed 3.1.10.7.2 Description of analysis sets
Safety and pharmacokinetic population in both trials Least square means ratios of impaired groups against the control group Linear regression against renal and hepatic function Descriptive statistics and handling of concentrations below the limit of quantification Safety analysis by descriptive statistics
3.1.10.8.1 Participant disposition
Trial AIC316-03-I-04: all 32 participants completed Trial AIC316-03-I-05: all 16 participants completed 3.1.10.8.2 Baseline characteristics
Trial AIC316-03-I-04: demographics by renal function group Trial AIC316-03-I-04: matching and estimated glomerular filtration rate ranges Trial AIC316-03-I-04: concomitant diseases and medications Trial AIC316-03-I-05: demographics by hepatic function group Trial AIC316-03-I-05: matching and Child-Pugh scores Trial AIC316-03-I-05: concomitant diseases and medications Trial AIC316-03-I-05: albumin, bilirubin, and prothrombin ranges in the impaired group 3.1.10.8.3 Efficacy results
Trial AIC316-03-I-04: least square means ratios for pritelivir, mild renal impairment against control Trial AIC316-03-I-04: least square means ratios for pritelivir, moderate renal impairment against control Trial AIC316-03-I-04: least square means ratios for pritelivir, severe renal impairment against control Trial AIC316-03-I-05: least square means ratios for pritelivir, moderate hepatic impairment against control Trial AIC316-03-I-04: pritelivir exposure by degree of renal impairment Trial AIC316-03-I-04: half-life and apparent clearance of pritelivir Trial AIC316-03-I-04: metabolite exposure by degree of renal impairment “For the metabolite PPA, the LS means ratios for AUCinf were 94.6%, 132.8%, and 296.9% for subjects with mild, moderate, and severe renal impairment compared with matched control subjects, respectively.” (opens the source at this quote in a new tab) Copy Flag
“For the metabolite ATS, the LS means ratios for AUCinf were 96.1%, 167.3%, and 259.7% and for the metabolite PPA-acyl glucuronide, the LS means ratios for AUC0-inf were 104.2%, 201.7%, and 559.4% for subjects with mild, moderate, and severe renal impairment compared with matched control subjects, respectively.” (opens the source at this quote in a new tab) Copy Flag
“Mean metabolite-to-parent ratios of AUC0-inf appeared to increase with severity level of renal impairment for all metabolites, this was most pronounced for PPA in the severe renal impairment group (Tables S2-S4).” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-04: correlation of exposure and clearance with estimated glomerular filtration rate Trial AIC316-03-I-04: authors' interpretation of pritelivir exposure in renal impairment Trial AIC316-03-I-04: authors' interpretation of metabolite exposure in renal impairment Trial AIC316-03-I-05: pritelivir exposure in moderate hepatic impairment Trial AIC316-03-I-05: fraction unbound in moderate hepatic impairment Trial AIC316-03-I-05: metabolite exposure in moderate hepatic impairment Trial AIC316-03-I-05: correlation of exposure with albumin, bilirubin, and prothrombin time Trial AIC316-03-I-05: authors' interpretation of exposure in moderate hepatic impairment Trial AIC316-03-I-04: descriptive pharmacokinetic parameters of pritelivir by renal function group Trial AIC316-03-I-05: descriptive pharmacokinetic parameters of pritelivir by hepatic function group Statistics shown in the descriptive parameter tables Authors' conclusions for both trials Prescribing information: pharmacokinetics in renal impairment Prescribing information: dosing in renal impairment Prescribing information: pharmacokinetics in hepatic impairment Prescribing information: dosing in hepatic impairment 3.1.10.8.4 Health-related quality of life and patient-reported outcomesNot applicable.
Trial AIC316-03-I-04: treatment-emergent adverse events by renal function group Trial AIC316-03-I-04: events by group and severity Trial AIC316-03-I-04: pattern of events and relatedness to pritelivir Trial AIC316-03-I-04: laboratory parameters, vital signs, and electrocardiograms Trial AIC316-03-I-05: treatment-emergent adverse events by hepatic function group Trial AIC316-03-I-05: events by preferred term and intensity Trial AIC316-03-I-05: laboratory parameters, vital signs, and electrocardiograms Authors' conclusion on safety in both trials 3.1.10.9 Study limitations
Summary Both trials were single-center, open-label, single-dose trials with 8 participants per group, all White; the 90% confidence interval of the Cmax ratio in mild renal impairment spanned 52.0% to 153.9%. The hepatic trial enrolled Child-Pugh stage B only, and 2 of 8 impaired participants had abnormal albumin, bilirubin, or prothrombin values. Regression lines against eGFR had low R2 values. Fraction unbound measured ex vivo (0.551% to 0.607% in controls) differed from the earlier in vitro value of 2.8%. Hemodialysis and severe hepatic impairment were not evaluated. The sponsor funded both trials.
Trial AIC316-03-I-04: low coefficients of determination in the regression on renal function Trial AIC316-03-I-05: limited range of hepatic function abnormalities Fraction unbound differing from earlier in vitro results Populations not evaluated: hemodialysis and severe hepatic impairment Funding and author affiliations 3.1.11 AIC316-01-I-04 and AIC316-03-I-02
Absorption, distribution, metabolism, and excretion of pritelivir in both trials Trial AIC316-01-I-04: mass balance and metabolite profile after multiple doses Trial AIC316-03-I-02: mass balance and metabolite profile after a single dose Purpose of a human mass balance trial 3.1.11.2 Location and study date
Trial sites of AIC316-01-I-04 and AIC316-03-I-02 Ethics committees and conduct standards in both trials
Trial AIC316-01-I-04: open-label, single-center, multiple-dose design Trial AIC316-01-I-04: steady-state conditions and the loading dose Trial AIC316-01-I-04: screening, confinement, and follow-up Trial AIC316-01-I-04: blood sampling schedule “Blood samples (3 mL at each time point) for PK analysis of pritelivir were collected predose from day 1 until day 8 and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 288, and 336 hours postdose on day 8.” (opens the source at this quote in a new tab) Copy Flag
“Blood samples (3 mL at each time point) for PK analysis of total radioactivity (TRA) were collected predose on day 1 and day 8, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 96, 144, 192, 240, 288, 336, 384, 432, 480, 528, 576, and 624 hours postdose on day 8.” (opens the source at this quote in a new tab) Copy Flag
“Blood samples (10 mL each time point) for metabolite profiling were collected at 2, 4, 24, 48, 96, 144, 192, 240, 288, 336, 384, 432, 480, and 624 hours postdose on day 8.” (opens the source at this quote in a new tab) Copy Flag
“Metabolite profiling was done using pooled plasma samples (0-24 hours).” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-01-I-04: urine and feces collection schedule “Urine and feces were collected to determine the recovery of TRA and for the identification of metabolites.” (opens the source at this quote in a new tab) Copy Flag
“Urine was collected predose on days 1 and 8 and postdose on day 8 between 0-4, 4-8, 8-12, 12-24, 48-96, 96-144, 144-192, 192-240, 240-288, 288-336, 336-384, 384-432, 432-480, 480-528, 528-576, and 576-624 hours.” (opens the source at this quote in a new tab) Copy Flag
“Feces were collected predose on day 1 and postdose on day 8 between 0 and 12 hours.” (opens the source at this quote in a new tab) Copy Flag
“Thereafter, feces collection intervals were the same as for urine.” (opens the source at this quote in a new tab) Copy Flag
“Metabolite profiling was done using pooled urine samples (0-192 hours) and pooled feces samples (24-240 hours).” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-02: open-label, single-center, single-dose design with two radiolabel positions Trial AIC316-03-I-02: reason for labeling both moieties Trial AIC316-03-I-02: screening, confinement, and follow-up Trial AIC316-03-I-02: blood sampling schedule “Blood samples for PK analysis of pritelivir and metabolites PPA, aminothiazole sulfonamide (ATS) and PPA-acyl glucuronide in plasma and blood (3 mL at each time point per matrix) were collected predose on day 1 and postdose at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 288, 336, 384, 432, 480, 528, 576, and 624 hours.” (opens the source at this quote in a new tab) Copy Flag
“Blood samples for PK analysis of TRA in plasma and blood (4 mL for plasma and 2 mL for blood) were collected predose on day 1 and postdose at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 288, 336, 384, 432, 480, 528, 576, and 624 hours.” (opens the source at this quote in a new tab) Copy Flag
“Additional blood samples of 4 mL were collected for metabolite profiling on day 1 postdose at 2, 4, 24, 480, and 624 hours.” (opens the source at this quote in a new tab) Copy Flag
“Metabolite profiling was done using pooled plasma samples (0-336 hours).” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-02: urine and feces collection schedule “Urine was collected on day 1 between 0-4, 4-8, 8-12, 12-24, 48-96, 96-144, 144-192, 192-240, 240-288, 288-336, 336-384, 384-432, 432-480, 480-528, 528-576, and 576-624 hours.” (opens the source at this quote in a new tab) Copy Flag
“Metabolite profiling was done using pooled urine samples (0-432 hours) and pooled feces samples (0-384 hours).” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-01-I-04: bioanalytical methods and lower limits of quantification Trial AIC316-03-I-02: bioanalytical methods and lower limits of quantification “Plasma and whole-blood concentrations of pritelivir were determined using a validated mass spectrometry, liquid chromatography method (HPLC-MS/MS) by A&M Labor für Analytik und Metabolismusforschung Service GmbH (Bergheim, Germany).” (opens the source at this quote in a new tab) Copy Flag
“The LLOQs for pritelivir, PPA, ATS, and PPA-acyl glucuronide in plasma and whole blood were 10.00, 2.00, 2.00, and 0.1 (plasma only) ng/mL, respectively.” (opens the source at this quote in a new tab) Copy Flag
“TRA in plasma, urine, and feces, was determined using AMS by TNO (Leiden, The Netherlands).” (opens the source at this quote in a new tab) Copy Flag
“The LLOQs for TRA were 1.65, 5.78, and 1.18 ng/eq/mL and 3.04 ng/eq/g in plasma, whole blood, urine, and feces, respectively.” (opens the source at this quote in a new tab) Copy Flag
“Metabolite identification was performed by TNO.” (opens the source at this quote in a new tab) Copy Flag
3.1.11.4 Eligibility criteria
Inclusion criteria: healthy men, with age and body mass index limits by trial Exclusion criteria in both trials: disease history and abnormal findings “Subjects with a history or current evidence of any clinically relevant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrinological, metabolic, neurological, psychiatric, or other disease or malignancy were excluded.” (opens the source at this quote in a new tab) Copy Flag
“Subjects were also excluded in case of any clinically relevant abnormalities in ECG, vital signs, clinical chemistry, hematological, or any other laboratory values.” (opens the source at this quote in a new tab) Copy Flag
Prior and concomitant medication restrictions in both trials Diet, smoking, and alcohol restrictions in both trials
Trial AIC316-01-I-04: pritelivir 500 mg on day 1, then 100 mg daily, with a radiolabeled microdose on day 8 Trial AIC316-03-I-02: single 100 mg dose of pritelivir with two radiolabeled tracers Formulations used in each trial
3.1.11.6.1 Rationale for using recovery of total radioactivity in urine and feces as the primary outcome
Radiolabeled microdose measured by accelerator mass spectrometry Excretion of total radioactivity as a percentage of the administered dose Trial AIC316-01-I-04: plasma pharmacokinetic parameters calculated “Trial 1. For pritelivir and TRA (dose-normalized to 100 mg) in plasma.” (opens the source at this quote in a new tab) Copy Flag
“On days 2-8: C0h (pritelivir only); on day 8: Cmin, Cmax (TRA only), Cmax,ss (pritelivir only), tmax, AUCτ,ss, AUC0-24, AUC0-last, AUC0-inf, t1/2z, CL/F (pritelivir only) and Vss/F (pritelivir only).” (opens the source at this quote in a new tab) Copy Flag
“In addition, the ratio of AUCτ,ss of pritelivir over AUC0-last and AUC0-inf of TRA in plasma was calculated.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-02: plasma and whole-blood pharmacokinetic parameters calculated “Trial 2. For pritelivir, metabolites and TRA (dose-normalized to 100 mg) in plasma and whole blood (PPA-acyl glucuronide in plasma only): Cmax, tmax, tlag, AUC0-last, AUC0-inf, t1/2z, CL/F (pritelivir only) and Vss/F (pritelivir only).” (opens the source at this quote in a new tab) Copy Flag
“In addition, blood to plasma (BP) ratios were determined for Cmax, AUC0-last, AUC0-inf and concentration per timepoint.” (opens the source at this quote in a new tab) Copy Flag
Safety and tolerability assessments in both trials 3.1.11.7 Statistical analysis description
3.1.11.7.1 Number of participants (Planned and analyzed)
Trial AIC316-01-I-04: participants enrolled and analyzed Trial AIC316-01-I-04: participants contributing to each parameter Trial AIC316-03-I-02: participants enrolled and analyzed 3.1.11.7.2 Description of analysis sets
Safety and pharmacokinetic population in both trials Noncompartmental analysis and descriptive statistics “For both trials PK analyses were performed with standard noncompartmental methods using the validated computer program Phoenix WinNonlin (version 4.1 and 8.1; Certara USA Inc., Princeton, New Jersey).” (opens the source at this quote in a new tab) Copy Flag
“PK parameters for pritelivir (free base) and metabolites (PPA, ATS, and PPA-acyl glucuronide) were calculated based on the individual plasma, whole-blood, urine, and feces concentration versus time data using the actual sampling and times and collection intervals.” (opens the source at this quote in a new tab) Copy Flag
“Descriptive statistics were calculated for the PK parameters of pritelivir and included sample size (n), mean, standard deviation (SD), coefficient of variation (% CV), geometric mean, median, minimum, and maximum.” (opens the source at this quote in a new tab) Copy Flag
Safety analysis by descriptive statistics
3.1.11.8.1 Participant disposition
Trial AIC316-01-I-04: one of 8 participants withdrew after the last dose Trial AIC316-03-I-02: all 6 participants completed 3.1.11.8.2 Baseline characteristics
Sex and health status of the enrolled participants in both trials Demographics reported in a supplementary table 3.1.11.8.3 Efficacy results
Recovery of total radioactivity in urine and feces over 0 to 624 hours in both trials Trial AIC316-01-I-04: recovery of the administered radioactive dose Trial AIC316-03-I-02: recovery of the administered radioactive dose Recovery, excretion route, and plasma composition as summarized in the abstract “The plasma half-life of pritelivir was 63-67 hours.” (opens the source at this quote in a new tab) Copy Flag
“Overall, 92% and 66% of the administered dose was recovered in the multiple and single dose trials, respectively.” (opens the source at this quote in a new tab) Copy Flag
“More than 90% of drug-related material was eliminated 624 hours postdose.” (opens the source at this quote in a new tab) Copy Flag
“The majority was excreted in urine (75% and 77%), followed by feces (16% and 23%).” (opens the source at this quote in a new tab) Copy Flag
“In plasma, pritelivir, ATS, PPA, and PPA-acyl glucuronide accounted for 40.6%, 9.4%, 5.1%, and 0.2% of total radioactivity.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-01-I-04: plasma pharmacokinetics of pritelivir and total radioactivity Trial AIC316-01-I-04: share of plasma radioactivity accounted for by pritelivir Trial AIC316-01-I-04: pharmacokinetic parameters of pritelivir and dose-normalized total radioactivity Trial AIC316-01-I-04: notes to the pharmacokinetic parameter table Trial AIC316-03-I-02: plasma and whole-blood pharmacokinetics of pritelivir and total radioactivity “After a single oral dose of unlabeled and 14C-labeled pritelivir, TRA was more rapidly absorbed compared to pritelivir.” (opens the source at this quote in a new tab) Copy Flag
“Mean plasma and whole-blood concentrations of both pritelivir and TRA peaked at 4 and 10 hours after dosing (Figure 5).” (opens the source at this quote in a new tab) Copy Flag
“Median tmax was at 7 and 7.5 hours for pritelivir and at 4 and 0.9 hours for TRA in plasma and whole blood, respectively.” (opens the source at this quote in a new tab) Copy Flag
“Mean concentrations of pritelivir and TRA declined more or less in parallel up to 336 hours, after which TRA appeared to decline at a slower rate, although samples could not be measured for pritelivir beyond 336 hours (below LLOQ).” (opens the source at this quote in a new tab) Copy Flag
“In plasma, the mean t1/2z values were 67.1 and 119 hours and in whole blood they were 76.5 and 95.6 hours for pritelivir and TRA, respectively (Table 3).” (opens the source at this quote in a new tab) Copy Flag
“The mean Cmax for TRA in plasma and whole blood was approximately 1.9- and 1.6-fold higher, respectively, compared to pritelivir, while for mean AUC0-last and AUC0-inf, TRA was approximately 2.4-fold higher in both plasma and whole blood.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-02: share of total radioactivity by analyte in plasma and whole blood Trial AIC316-03-I-02: whole-blood to plasma ratios Trial AIC316-03-I-02: plasma pharmacokinetic parameters of pritelivir, metabolites, and total radioactivity Trial AIC316-03-I-02: whole-blood pharmacokinetic parameters of pritelivir, metabolites, and total radioactivity Trial AIC316-03-I-02: apparent clearance of pritelivir Trial AIC316-01-I-04: metabolite identification in plasma Trial AIC316-01-I-04: metabolite identification in urine Trial AIC316-01-I-04: metabolite identification in feces Trial AIC316-03-I-02: metabolite identification in plasma Trial AIC316-03-I-02: metabolite identification in urine “In pooled urine collected between 0 and 432 hours postdose, a total of 12 pritelivir-related peaks were detected.” (opens the source at this quote in a new tab) Copy Flag
“The main component in urine was identified as PPA-β-1-acyl glucuronide, accounting for 29.6% of TRA present (44.5% of the recovered dose).” (opens the source at this quote in a new tab) Copy Flag
“Three isomers of PPA-acyl glucuronide accounting for 2.0%-3.4% were also detected (3.0%-5.1% of the recovered dose).” (opens the source at this quote in a new tab) Copy Flag
“In total, PPA-acyl glucuronide and isomers accounted for 38.2% of the TRA in urine (57% of the recovered dose).” (opens the source at this quote in a new tab) Copy Flag
“ATS accounted for 23.1% of TRA (34.7% of the recovered dose).” (opens the source at this quote in a new tab) Copy Flag
“An additional metabolite was tentatively identified as N-demethylated ATS, accounting for 12.8% of the TRA (19.2% of the recovered dose).” (opens the source at this quote in a new tab) Copy Flag
“PPA accounted for 2.1%, hydroxylated pritelivir accounted for 1.9%, and pritelivir accounted for 0.6% (3.2%, 1.4%, and 0.5% of the recovered dose, respectively).” (opens the source at this quote in a new tab) Copy Flag
“Four minor metabolites were tentatively assigned to N-demethylated ATS (2.0%), hydroxylated and glucuronidated pritelivir (1.1%), glucuronidated pritelivir (2.1%), and hydroxylated PPA (1.5%).” (opens the source at this quote in a new tab) Copy Flag
“In urine, 84.9% of TRA was assigned to peaks with relative abundances above 1%.” (opens the source at this quote in a new tab) Copy Flag
Trial AIC316-03-I-02: metabolite identification in feces Urinary PPA-acyl glucuronide compared between the trials Metabolic pathways proposed from both trials Distribution into red blood cells Authors' conclusions from both trials “In conclusion, the overall recovery of 92% within 624 hours after dose administration with the main elimination route being renal as determined in Trial 1 is deemed adequate to describe the overall elimination time course of drug-related material.” (opens the source at this quote in a new tab) Copy Flag
“Pritelivir was the main component in plasma, representing 41%-48% of the TRA.” (opens the source at this quote in a new tab) Copy Flag
“PPA, ATS, and PPA-acyl glucuronide represented 9.4%, 5.1%, and 0.2% of the TRA in plasma, respectively.” (opens the source at this quote in a new tab) Copy Flag
“The acyl glucuronide of PPA and its isomers next to ATS and its N-demethylated isomers were the main metabolites in the urine.” (opens the source at this quote in a new tab) Copy Flag
“In feces, pritelivir (representing most likely unabsorbed pritelivir) and its hydroxylated form were the main components.” (opens the source at this quote in a new tab) Copy Flag
“In conclusion, these 2 human mass balance trials showed that pritelivir was largely metabolized, with the primary route of excretion being renal.” (opens the source at this quote in a new tab) Copy Flag
“Based on the assigned metabolites, pritelivir underwent mainly amide hydrolysis and (further) glucuronidation and N-demethylation.” (opens the source at this quote in a new tab) Copy Flag
Prescribing information: metabolism and excretion of pritelivir Prescribing information: mass balance study described in the table notes 3.1.11.8.4 Health-related quality of life and patient-reported outcomesNot applicable.
Trial AIC316-01-I-04: treatment-emergent adverse events Trial AIC316-01-I-04: headache, migraine, and withdrawal Trial AIC316-01-I-04: events considered unlikely to be related Trial AIC316-03-I-02: treatment-emergent adverse events 3.1.11.9 Study limitations
Summary The trials enrolled 8 and 6 healthy men in open-label, single-center designs. In the single-dose trial, 66.0% of the radioactive dose was recovered, which the authors attribute to slow capsule dissolution and incomplete absorption; plasma exposure was about 2-fold lower than in previous trials. In the multiple-dose trial, the single label position left some metabolites undetectable, fecal extraction efficiency was 37.4%, one participant withdrew before collections ended, and AUC0-inf of total radioactivity could not be determined accurately for 5 of 8 participants. The cause of the second elimination phase of total radioactivity was not identified. The sponsor funded both trials.
Trial AIC316-03-I-02: incomplete recovery of the radioactive dose Trial AIC316-03-I-02: causes of incomplete recovery that the authors examined Trial AIC316-03-I-02: slow dissolution of the capsule and incomplete absorption Trial AIC316-03-I-02: lower plasma exposure than in previous trials Trial AIC316-01-I-04: metabolites undetectable with one radiolabel position Trial AIC316-01-I-04: low extraction efficiency from feces Trial AIC316-01-I-04: total radioactivity exposure and half-life not accurately determined Second elimination phase of total radioactivity of unidentified cause Funding and author affiliations 3.1.12 First-in-human phase 1 trials
Evaluation of pharmacokinetics and safety in five phase 1 trials 3.1.12.2 Location and study dateNo evidence found.
Types of trials reported in the publication Trial numbers of earlier phase 1 trials named in the thorough QT trial protocol 3.1.12.4 Eligibility criteria
Healthy women in the single-ascending-dose trial Sex of participants in trial AIC316-01-I-05, as stated in the thorough QT trial protocol
Multiple-dose regimens of trial AIC316-01-I-05, as stated in the thorough QT trial protocol High-fat meal composition for the food effect value in the prescribing information
3.1.12.6.1 Rationale for using safety and pharmacokinetics as the primary endpointsNo evidence found.
3.1.12.7 Statistical analysis description
3.1.12.7.1 Number of participants (Planned and analyzed)No evidence found.
3.1.12.7.2 Description of analysis setsNo evidence found.
3.1.12.8.1 Participant dispositionNo evidence found.
3.1.12.8.2 Baseline characteristicsNo evidence found.
3.1.12.8.3 Efficacy results
Dose linearity after single and multiple doses Half-life and time to steady state Exposure in women compared with men Prescribing information values for absolute bioavailability, food effect, time to maximum concentration, and half-life Prescribing information statements on dose proportionality and steady state Prescribing information statement on pharmacokinetics by sex “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).” (opens the prescribing information at this quote) Copy Flag
Sponsor summary of earlier single-dose and multiple-dose pharmacokinetics in the thorough QT trial protocol 3.1.12.8.4 Health-related quality of life and patient-reported outcomesNot applicable.
Tolerability by single and multiple dose Skin reactions at 400 mg once daily in trial AIC316-01-I-05, as stated in the thorough QT trial protocol Sponsor summary of clinical experience at supratherapeutic doses in the thorough QT trial protocol 3.1.12.9 Study limitations
Summary The publication of the five trials is quoted from its PubMed abstract. The abstract gives no enrollment counts, trial numbers, sites, dates, or adverse event rates. Participants were healthy men, with 1 cohort of healthy women in the single-ascending-dose trial. The abstract reports tolerability up to 200 mg once daily with multiple dosing. The sponsor's thorough QT trial protocol, dated 25 November 2022, describes trial AIC316-01-I-05, which was stopped early after skin reactions in 5 of 16 participants in the 400 mg dose group (4 of 12 receiving pritelivir and 1 of 4 receiving placebo).