Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety

This article is featured in Highlights of This Issue, p. 289

Endogenous and exogenous mutagens consistently damage the DNA in normal cells (1). The DNA is protected by robust DNA repair and damage-bypass mechanisms (2). Nevertheless, as DNA repair systems are not perfect, genetic and epigenetic alterations can accumulate in the DNA (3, 4). Function-altering mutations and continuous genomic instability have been described as characteristics that induce tumor pathogenesis and progression (5). In addition, inherited or somatically acquired genetic alterations in DNA repair genes may promote tumorigenesis (3). A combination of genetic and clinical evaluation is generally used to determine the best course of action for patients (6). Therefore, genetic testing is commonly conducted to make treatment decisions for patients with cancer (7).

PARP is an enzyme that plays a key role in DNA repair, transcription, apoptosis, and immune function (8). PARP-1 recruits synthetic DNA enzymes to activate DNA recovery (9). PARP-2 maintains genomic stability and repairs DNA single-strand breaks (SSB; ref. 10). Both PARP-1 and PARP-2 share regulatory mechanisms in DNA repair systems but differ in the mechanism by which they bind to DNA breaks (11). Thus, inhibition of PARP-1/2 results in DNA SSBs and promotes the conversion of SSBs to double-strand breaks (DSB), which induces synthetic lethality in cancer cells due to the lack of homologous recombination (HR; ref. 12). As such, BRCA1- and BRCA2-defective tumors are intrinsically sensitive to PARP inhibition (13). The PARP–BRCA interaction is an example of a successful synthetically lethal approach. To date, four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) have been approved by the FDA for various indications (14).

However, 54% of patients treated with olaparib have been reported to experience adverse events (AE) of ≥grade 3 as per the Common Terminology Criteria for Adverse Events (15). The most frequent grade 3 or worse treatment-emergent AEs are hematologic toxicities such as anemia, thrombocytopenia, and neutropenia (16–18). The common nonhematologic AEs associated with PARP inhibitors are fatigue, nausea, and vomiting (15). The difference in hematologic toxicities among PARP inhibitors may be related to their action on PARP-3 (19). PARP-3 inhibition damages non-homologous end joining DNA repair system, which increases apoptosis of hematopoietic stem cells and multipotent progenitor cells. In addition, inhibition of PARP-5A, also known as tankyrase-1, leads to the loss of bone density with increased osteoclasts and reversible intestinal toxicity (20, 21).

Another important factor that regulates the efficacy and safety of PARP inhibitors is in their ability to trap PARP. Until the PARP inhibitor dissociates from the active site, PARP-1 and PARP-2 are effectively trapped on the DNA (22). As PARP trapping is mediated by the presence of PARP, it is mechanistically dependent on PAR formation or enzymatic inhibition. PARP trapping contributes to the variation in toxicity among PARP inhibitors (23). Therefore, it is important to identify PARP inhibitors with a balanced PARP trapping activity for maximal therapeutic advantages.

We had synthesized a series of derivatives based on the chemical structure of phthalazine; in our in-house studies, venadaparib (code name: IDX-1197, NOV140101) was the most prominent during the discovery phase. Hence, in this study, we evaluated the physicochemical properties, efficacy, and safety of venadaparib, a novel and highly selective PARP inhibitor.

All applications in the molecular docking simulation were provided in the Maestro module of Schrödinger Suite 2020-3. The X-ray crystal structure of the PARP-1/olaparib complex was acquired from the Protein Data Bank (PDB ID: 5DS3; ref. 24). The receptor grid was generated in a 20 × 20 × 20 Å space region centered at the coligand of the complex structure. Thereafter, energy-minimized three-dimensional structure of venadaparib was docked with default values in the SP mode using Glide. The protein–ligand interactions were analyzed using Discovery Studio Modeling Environment v4.026 (BIOVIA) and the docking models were displayed using PyMOL v2.0.47 (Schrödinger Suite).

The effects of venadaparib on recombinant human PARP enzymes (PARP-1, PARP-2, PARP-3, TNKS-1, TNKS-2, PARP-6, PARP-7, PARP-8, PARP-10, PARP-11, PARP-12, PARP-14, and PARP-15) were determined using in vitro enzymatic assays performed by BPS Bioscience. Venadaparib was examined at concentrations ranging from 0.000005 to 10 μmol/L. Luminescent outputs were measured using a Synergy 2 microplate reader (BioTek Instruments). IC₅₀ was determined using Prism 9 (GraphPad Software).

Venadaparib and olaparib were synthesized at research laboratories of Ildong Pharmaceutical. Experimental details for the synthesis of venadaparib were described in U.S. patent application publication (publication no. US 2021/0323946 A1; example 12, Supplementary Fig. S1; ref. 25). Rucaparib (catalog no. S1098; Selleck Chemicals), niraparib (catalog no. CT-MK4827; ChemieTek), talazoparib (catalog no. S7048; Selleck Chemicals), and veliparib (catalog no. S1004; Selleck Chemicals) were purchased from commercial vendor, respectively. All compounds were dissolved in DMSO. HeLa cells (Korea Cell Line Bank, Seoul, Republic of Korea) were treated with the above compounds at doses ranging from 0.01 to 100 nmol/L (final concentration of less than 1% DMSO). HeLa cells were then treated with hydrogen peroxide to induce DNA damage. The luminescence signals were detected in the HeLa cells using a PAR antibody on a Synergy H4 hybrid microplate reader (BioTek Instruments) and normalized to the number of cells per plate. The value of the DMSO-only control group was calculated to be 100%. Measurements for each concentration of the test substances were calculated as percentages relative to those of the control group.

The effects of venadaparib on the DNA-binding activities of the recombinant human PARP-1 enzyme were determined using an in vitro enzymatic assay performed by BPS Bioscience. The PARPtrap assay kit (catalog no. 80584; BPS Bioscience) was used for the assay. Venadaparib, olaparib, rucaparib, niraparib, talazoparib, and veliparib were examined at concentrations ranging from 0.000026 to 5 μmol/L. After enzymatic reactions according to the manufacturer's instructions, fluorescent signals were measured using an M1000 microplate reader (Tecan Infinite) with an excitation wavelength of 485 nm and an emission wavelength of 528 nm.

Stock solutions of the test molecules were serially diluted separately with DMSO for use in three ovarian cancer cell lines (IGROV-1, SK-OV-3, and OVCAR-3), three breast cancer cell lines (MDA-MB-453, HCC1569, and MX-1), one pancreatic cancer cell line (CAPAN-1), and one gastric cancer cell line (KATOIII) at varying treatment concentrations (Supplementary Table S1). The cells were treated such that the final concentration of DMSO, which was used as the solvent to dissolve the compounds, was less than 1%. The cells were treated with the compounds (venadaparib: 0.03 to 50,000 nmol/L or olaparib: 0.64 to 50,000 nmol/L) and maintained at 37°C in a 5% CO₂ incubator. They were left undisturbed for 11 to 30 days (depending on the characteristics of each cell type on PARP inhibitory effect) until colonies appeared. Thereafter, the colonies were stained with a mixture of crystal violet and glutaraldehyde, and the colonies were counted. The test results were calculated as the percentage of the colony number at each concentration of the compound relative to that of the control group (100%), in which only the solvent was added.

Animal studies were conducted in various sites. All studies were performed in accordance with the guidelines established by the U.S. NIH Animal Research and Care and approved by the Institutional Animal Care and Use Committee of each site. A pharmacokinetic study and an animal study using CAPAN-1 cell line–derived xenograft (CDX) models were carried out in the research laboratories of Ildong Pharmaceutical. Animal studies using MX-1 CDX and the OV_065 (high-grade serous ovarian cancer, germline BRCA1 mutation; p.Glu1257Glyfs*p) patient-derived xenograft (PDX) models were performed by Crown Bioscience Inc. and by Asan Medical Center (Seoul, Republic of Korea), respectively. The chronic toxicity study in rats was conducted at Covance Laboratories.

For the OV_065 PDX model, OV_065 cancer tissue was implanted less than 1 mm into the subcutaneous pocket of the right flank of athymic nude mice (female, 6 weeks old, total 40 mice, n = 8/group). To establish the CDX model, BALB/c nude mice (female, 7–8 weeks old) were inoculated subcutaneously in the right flank region with MX-1 (5 × 10⁶ cells/mouse, total 50 mice, n = 10/group) or CAPAN-1 (1 × 10⁷ cells/mouse, total 48 mice, n = 8/group). Tumor size was assessed twice a week as (length × width²)/2 using calipers. When the mean tumor size reached a volume of 100–250 mm³, the mice were assigned to each study group in such a way that intergroup differences in mean tumor size were minimized. The mice were orally administrated venadaparib HCl (12.5–50 mg/kg to the OV_065 and MX-1 models, 50–200 mg/kg to the CAPAN-1 model) or olaparib (50–100 mg/kg). Morbidity and mortality were checked once daily. To compare tumor growth trends among the test groups, tumor growth inhibition (TGI; %) was calculated as 100 − (100 × (T − T₀)/(C − C₀)); T = mean tumor volume of the drug treatment group on the final day; T₀ = mean tumor volume of the drug treatment group at the start of treatment; C = mean tumor volume of the vehicle control group on the final day; C₀ = mean tumor volume of the vehicle control group at the start of treatment. Body weight was measured twice a week, and mice were euthanized when their tumor volume reached over 2,000 mm³ or they lost over 20% of their body weight.

Female Institute of Cancer Research (ICR) mice (18–22 g, 6–7 weeks old) were used to evaluate the pharmacokinetic properties of venadaparib. Nine mice received a single 20 mg/kg intravenous dose of venadaparib HCl via the tail vein. Six fasted mice received a single 60 mg/kg oral dose of venadaparib HCl. Food was supplied 4 hours after dosing. Blood was collected at the following time schedule: intravenous group: 5, 10, 15, 30, 60, 120, and 240 minutes after dosing; oral group: 15, 30, 60, 120, and 240 minutes after dosing. The plasma concentrations of venadaparib were determined using LC/MS-MS (Agilent 1290 Infinity; Agilent Technologies), after protein precipitation with acetonitrile containing an internal standard and centrifugation at 13,000 rpm for 5 minutes at 4°C.

The OV_065 PDX model was used for the pharmacokinetic/pharmacodynamic study. The mice were divided into four groups (n = 4/group), treated with venadaparib HCl once daily (12.5 mg/kg) for 7 days, and then euthanized at 4, 7, and 24 hours after dosing. One vehicle control group, treated only with distilled water, was euthanized 4 hours after administration. Following euthanasia using CO₂ gas at the indicated timepoints, plasma and tumor samples were collected and shipped to the research laboratories of Ildong Pharmaceutical, and stored at −70°C. The concentrations of venadaparib in the plasma and tumor tissues were determined using the method described above. To examine the pharmacodynamic activity of venadaparib, we measured intratumoral PAR levels using an HT PARP in vivo pharmacodynamic assay II kit (catalog no. 4520-096-K; R&D Systems).

In the 4-week toxicity and toxicokinetic (TK) studies, Wistar Han rats (male and female, n = 10/sex/group for toxicity groups, 3 or 6/sex/group for TK groups) were administered vehicle or venadaparib HCl at 15, 30, or 60 mg/kg (as venadaparib) daily; recovery animals (n = 5/sex/group) were treated alongside toxicity groups followed by a 4-week off-dose period. We determined hemoglobin level, hematocrit ratio, erythrocyte, neutrophil, platelet, and absolute reticulocyte counts to evaluate hematologic values.

The experiment for bone marrow toxicity of venadaparib was performed at Stemcell Technologies. Bone marrow–derived hematopoietic progenitor cells from three lots of human bone marrow mononuclear cells were incubated with venadaparib (0.000169–30 μmol/L) or a control compound, 5-fluorouracil (F6627; Sigma-Aldrich), in MethoCult GF H84434 (catalog no. 84434; Stemcell Technologies) at 37°C in a 5% CO₂ incubator. After 14 days, the hematopoietic colonies were assessed and scored by trained personnel. The mean colony number was calculated for triplicate cultures under each condition and normalized to the solvent controls. Standard t tests were performed to compare the solvent controls for each test compound. Because of the potential subjectivity of colony enumeration, a P value of less than 0.01 was considered significant.

The selectivity profile of venadaparib on diverse panels covering 88 kinds of enzymes and receptors involved in the cardiovascular, respiratory, and nervous systems was performed at Eurofins Panlabs. Screening was performed using either a radioligand binding assay or an enzymatic assay. Venadaparib was tested at 10 μmol/L in duplicate, and results showing relative inhibition higher than 50% were considered to be significant. Relative inhibition ranging from 25% to 50% was indicative of weak to moderate effects, and results showing a relative inhibition lower than 25% were not considered significant.

The results are presented as mean ± SD and processed using GraphPad Prism 9. All results represent the average of at least three independent experiments. Unless otherwise stated, statistical comparisons between the control and each treatment group were performed using a one-way or two-way analysis of variance followed by Dunnett test. Statistical significance was set at P < 0.05.

The data generated in this study are available upon request from the corresponding author.

Venadaparib exhibited appropriate drug-likeness, adhering to Egan's and Pfizer's 3/75 rule (26, 27). The binding mode of venadaparib to PARP-1 and its physicochemical properties are presented in Fig. 1.

The enzyme-inhibiting activities of venadaparib were tested to assess its selectivity for recombinant PARP enzymes. As shown in Table 1A, venadaparib selectively inhibited PARP-1/2 with IC₅₀ values of 0.8 and 3 nmol/L, respectively. The IC₅₀ values determined for venadaparib against other PARP enzymes were 780 nmol/L for PARP-3 and 3,200 nmol/L (62% inhibition at 10 μmol/L) for TNKS-2; venadaparib did not affect TNKS-1 and PARP-6/7/8/10/11/12/14/15 up to 10,000 nmol/L. The data revealed that venadaparib is highly selective for PARP-1/2.

The PAR formation inhibitory activity of venadaparib was assessed by the cellular PARP-1–inhibiting activity of venadaparib. As shown in Table 1B, venadaparib effectively inhibited the synthesis of PAR at an EC₅₀ of 0.5 nmol/L measured in a HeLa cell line where DNA damage was induced. This value was similar to that of olaparib (EC₅₀ = 0.7 nmol/L) and talazoparib (EC₅₀ = 0.7 nmol/L), whereas rucaparib, niraparib, and veliparib showed relatively low activities (EC₅₀ values of 1.9, 5.6, and 4.5 nmol/L, respectively).

An in vitro enzymatic assay using fluorescence polarization showed that venadaparib (EC₅₀ = 2.2 nmol/L) has a trapping activity similar to that of talazoparib (EC₅₀ = 1.9 nmol/L). The ability of venadaparib to trap PARP was higher than that of other PARP inhibitors (EC₅₀ = 6.4–118.0 nmol/L; Table 1B).

In the colony formation assay using genetically well-annotated cancer cell lines with or without mutations in the BRCA genes, venadaparib showed better inhibitory activity of colony formation than that of olaparib in cancers with mutations in BRCA1 and BRCA2; both compounds showed a decrease in efficacy against cell lines with wild-type BRCA genes (Table 2).

The pharmacokinetic characteristics of venadaparib were determined in healthy female ICR mice (Fig. 2A). Venadaparib has a high steady-state volume of distribution (V_ss = 5.28 L/kg) and a terminal elimination half-life of 0.90 hours. Venadaparib was rapidly absorbed, and the maximum plasma concentration was reached within 0.25 hours after dosing. The oral bioavailability of the solution formulation was 70.63%.

Oral administration of venadaparib HCl at a dose of 12.5 mg/kg considerably reduced tumor PAR levels by over 90% until 24 hours after dosing in the OV_065 PDX model. Drug concentrations remained over 100 ng/g at 24 hours after administration in the tumor, whereas it was close to being below the lower limit of quantification (1 ng/mL) in the plasma (Fig. 2B). Treatment with venadaparib HCl induced a significant tumor regression (Fig. 2C). Treatment with venadaparib HCl at doses of 12.5, 25, and 50 mg/kg and olaparib at 50 mg/kg showed TGI rates of 131.0%, 132.7%, 135.2%, and 118.2%, respectively. Tumors completely disappeared in 50% of animals in the group treated with 50 mg/kg venadaparib.

In the MX-1 CDX model, the inhibitory effect of venadaparib on tumor growth was assessed using TGI. The TGI of groups treated with venadaparib HCl at doses of 12.5, 25, and 50 mg/kg was 43.8%, 62.9%, and 71.0%, respectively. The group treated with 12.5 mg/kg venadaparib HCl (TGI = 43.8%) had similar tumor growth patterns as the group treated with 100 mg/kg olaparib (TGI = 41.7%; Fig. 2D). In the CAPAN-1 CDX model, the TGI was 62.2%, 82.5%, and 110.7% in the groups treated with venadaparib HCl at 50, 100, and 200 mg/kg, respectively (Fig. 2E). Venadaparib regulated tumor growth in a dose-dependent manner. The group treated with 100 mg/kg venadaparib HCl (TGI = 82.5%) seemed to show higher TGI than the group treated with 100 mg/kg olaparib (TGI = 36.0%). The group treated with 200 mg/kg venadaparib HCl (TGI = 110.7%) presented the highest antitumor effect. None of the dosing groups had test drug-related deaths or any other general symptoms throughout the study period.

The 4-week toxicity and TK of venadaparib were investigated in male and female Wistar Han rats by dosing at 15, 30, or 60 mg/kg daily for 4 weeks via oral gavage. No unscheduled deaths or abnormal changes in clinical signs were observed during the study. The no-observed-adverse-effect-level (NOAEL) of venadaparib was 30 mg/kg/day in rats. In the hematologic examination following 4 weeks of repeated administration, significant decreases in erythrocyte count, hemoglobin level, and hematocrit ratios were observed at a dose of 60 mg/kg in males and ≥15 mg/kg in females (Table 3A). None of the groups dosed with venadaparib showed a decline in neutrophil/platelet counts or in absolute reticulocyte counts (immature red blood cells), except females treated with 60 mg/kg. The platelet counts increased in males at 60 mg/kg and females at 15 mg/kg or more. This response had resolved by the recovery period (Supplementary Table S2). Reductions in red cell mass, related to erythrocyte count, hemoglobin level, and hematocrit ratio at 15 and 30 mg/kg in female rats did not influence the NOAEL as a complete recovery (no significant difference from the control group; Supplementary Table S2) was made after the 4-week recovery period. In the clinical chemistry, venadaparib did not cause an increase in creatinine, aspartate aminotransferase, and alanine aminotransferase levels in both sexes following 28 days of repeated oral administration (Supplementary Table S2). The TK characteristics of venadaparib are presented in Table 3B.

We assessed bone marrow toxicity through continuous incubation for 14 days with venadaparib at various concentrations (0.000169, 0.000508, 0.00152, 0.00457, 0.0137, 0.041, 0.12, 0.37, 1.11, 3.33, 10, and 30 μmol/L) on three lots of human bone marrow–derived stem and progenitor cells for erythroid and myeloid colony proliferation in MethoCult GF H84434 (Fig. 3A). The average IC₅₀ of venadaparib in total colony-forming cells was 0.1006 μmol/L.

In the secondary pharmacology test, venadaparib at 10 μmol/L did not show significant off-target activity (defined as ≥50% inhibition) in any of the enzymes and receptors tested. In addition, venadaparib weakly to moderately inhibited monoamine oxidase MAO-B (37% inhibition), acetylcholinesterase (37% inhibition), adrenergic alpha 2A (25% inhibition), and 5-hydroxytryptamine1A (25% inhibition). These data revealed that venadaparib has a low potential to cause undesirable pharmacodynamic effects on physiologic functions (Fig. 3B).

Venadaparib is a novel and selective PARP inhibitor currently in clinical development. To the best of our knowledge, this is the first report on the physicochemical and nonclinical pharmacologic effects of venadaparib. The results showed that venadaparib has potent anticancer activities in both in vitro and in vivo models with favorable physicochemical and pharmacokinetic properties, as well as a toxicologic profile.

The remarkable characteristics of venadaparib include its high solubility, extensive tumor distribution, potent antitumor effects, and broad tolerability. Venadaparib exhibited appropriate physicochemical properties by adhering to Egan's and Pfizer's 3/75 rule (26, 27). These characteristics resulted in promising pharmacologic and toxicologic aspects, as discussed below.

PARP-1 and -2 are enzymes that repair DNA damage and maintain genomic stability. Inhibition of PARP-1 and -2 has shown promising antitumor effects, whereas undesirable inhibition of PARP-3 or -5 can induce adverse effects, including hematotoxicity and bone loss (9, 10, 20, 21). Enzymatic assays using various PARPs showed that venadaparib specifically affects PARP-1 and -2 (PARP-1 IC₅₀ = 0.8 nmol/L; PARP-2 IC₅₀ = 3 nmol/L) compared with olaparib (PARP-1 IC₅₀ = 0.6 nmol/L; PARP-2 IC₅₀ = 0.5 nmol/L; PARP-3 IC₅₀ = 14 nmol/L). In addition, it has been reported that approved PARP inhibitors suppress other PARP enzymes as well as PARP-1 and -2 (talazoparib: PARP-3 IC₅₀ = 62.8 nmol/L, TNKS-2 IC₅₀ = 108 nmol/L, rucaparib: PARP-3 IC₅₀ = 512 nmol/L; TNKS-1 IC₅₀ = 144 nmol/L; ref. 28). Inhibition of PAR formation and trapping on the DNA/PARP complex are the major mechanisms that lead to tumor cell death by PARP inhibitors (22). PARP inhibitors interfere with the repair of SSBs by trapping the DNA/PARP complex, resulting in DNA DSBs, which require an alternative pathway for repair (14, 29). The ability of venadaparib to inhibit PAR formation (EC₅₀ = 0.5 nmol/L) was comparable with that of olaparib (EC₅₀ = 0.7 nmol/L). The PARP trapping activity of venadaparib (EC₅₀ = 2.2 nmol/L) was demonstrated to be similar to that of talazoparib (EC₅₀ = 1.9 nmol/L) and more potent than that of other PARP inhibitors (EC₅₀ values ranged from 6.4 to 118.0 nmol/L).

Germline mutations in HR-related genes such as BRCA1 and BRCA2 are critical for the accumulation of DNA damage, inducing DNA DSBs (30). BRCA-deficient tumor cells diminished the ability to rescue DNA DSBs by HR, and in the absence of an alternative repair mechanism, such a deficiency leads to cell death (31). Inhibition of PARP, which is a known therapeutic strategy for BRCA1/2-deficient cancer, shows high sensitivity against cancers that have lost the ability to repair DNA breaks through the HR-related pathway (13). It was observed that venadaparib has approximately 40–440 times potent antitumor potency than olaparib in BRCA-mutated tumor cell lines. This inhibitory effect vanishes in tumor cells with wild-type BRCA. In other words, venadaparib is highly selective for BRCA-mutated cancer cells over BRCA wild-type cancer cell lines compared with olaparib. In particular, we confirmed that PARP inhibitor–induced tumor cell death depends on pathogenic BRCA mutations in CAPAN-1 cells. Although CAPAN-1 cells have a BRCA2 mutation, tumor growth inhibition by venadaparib was weakened due to the amplification of wild-type BRCA1.

Here, venadaparib was characterized by a high steady-state volume of distribution (V_ss = 5.28 L/kg). After a single oral dose of 60 mg/kg venadaparib HCl, venadaparib was rapidly absorbed and cleared from the blood. Our preliminary studies indicate that venadaparib is a potential substrate of efflux transporters (i.e., MDR1, BCRP). However, the venadaparib concentration in the tumor remained high (over 100 ng/g) even at 24 hours after dosing with only 12.5 mg/kg venadaparib HCl in the OV_065 PDX model. These distribution characteristics may be due to the basicity of venadaparib originating from the secondary amine, which was designed to enhance tumor penetration. Inhibition of intratumoral PAR remained over 90% until 24 hours after administration of 12.5 mg/kg venadaparib HCl. Moreover, the tumor:plasma partition coefficient (i.e., |$ {K}_{p,tumor:plasma} = \ \frac{{AU{C}_{tumor}}}{{AU{C}_{plasma}}}$|⁠) of venadaparib was 10.0, suggesting that venadaparib tends to more concentrate in tumor tissue than olaparib and niraparib (i.e., 0.33 for olaparib, and 5.19 for niraparib in the OVC135 PDX model; ref. 32). Notably, in the OV_065 PDX model, we observed complete tumor regression by venadaparib HCl, administered orally for a maximum of 63 days (50 mg/kg, once daily) in female mice. This result is consistent with a previous study finding that maintaining the PAR inhibition levels above 90% for 24 hours is important to completely eliminate the tumor (33).

The tumor regressive effects of venadaparib were demonstrated in other xenograft models using MX-1 and CAPAN-1. The data consistently indicated that venadaparib exhibited significant tumor growth-suppressive effects in a dose-dependent manner and had greater antitumor potency than olaparib. There were no abnormal clinical signs or body weight changes during the process.

Another compelling characteristic of venadaparib is its refined toxicity profile. It has been reported that the NOAEL of olaparib after 4 weeks of daily repeated oral dosing in rats is 15 mg/kg/day (33). Following 4 weeks of dosing at the NOAEL, the exposure (AUC_{0–24 h}) was 1.057 and 6.267 μg·h/mL in male and female rats, respectively. Safety margins from exposure to the effective dosage of olaparib (80 mg/kg, AUC_0-inf = 14.408 and 12.574 μg·h/mL in males and females, respectively) were calculated to be 0.07 and 0.5 times. In the rat 28-day repeat dose toxicity study of talazoparib, the highest nonseverely toxic dose was 0.05 mg/kg/day, (NOAEL is not determined); C_max = 0.0195 μg/mL, AUC = 0.148 μg·h/mL at 0.05 mg/kg, once daily on day 28 (34). Talazoparib showed superior anticancer effect in the MX-1 xenograft model at 0.33 mg/kg dose; however, the dose seems to be intolerable to mice as the AUC_{0–6 h} of talazoparib was in range of 0.075–128 μg·h/mL in mice at 0.15 mg/kg dose (35). In the 4-week TK study of venadaparib, drug exposure (AUC_{0–24 h}) at the NOAEL (30 mg/kg/day) was 11.60 and 10.70 μg·h/mL in male and female rats, respectively. Assuming the linear pharmacokinetics in mice, 100 mg/kg venadaparib in mice was estimated to be equivalent to NOAEL in female rats. Considering the safety margin of olaparib, 200 mg/kg venadaparib could have the same safety margin for rodents.

PARP inhibitors disrupt cell division and are therefore expected to have the greatest effect on rapidly dividing cells, as is common in the bone marrow, lymphoid, skin, and gastrointestinal tract tissue (36). Venadaparib also showed mild changes in hematology values after 4 weeks of repeated dosing up to 30 mg/kg; however, it was resolved during the off-dose recovery period. To further study the hematologic toxicity of venadaparib, we measured erythroid and myeloid colony proliferation using human bone marrow–derived stem and progenitor cells. Taken together, venadaparib inhibited colony growth of bone marrow–derived hematopoietic progenitor cells with an IC₅₀ of 0.1006 μmol/L, which is 200-fold greater than the EC₅₀ value of venadaparib in the inhibition of PAR formation. Hopkins and colleagues suggested that the PARP-trapping activities associated with greater cytotoxic potency may limit the therapeutic advantages of PARP inhibitors (23). It was verified that the resolution between PAR inhibition and cytotoxicity covers about a 100-fold gap for olaparib, rucaparib, and veliparib, but less than a 2-fold difference for talazoparib. This result could help reduce the incidence of adverse drug reactions that characterize and identify secondary pharmacology profiling of drug candidates (37). There were no significant off-target activities of venadaparib in the secondary pharmacology test at a concentration of 10 μmol/L. These results suggest that venadaparib is a novel PARP inhibitor with a lower possibility of unexpected adverse effects in the range of pharmacologically active doses.

In this study, we evaluated the nonclinical properties of venadaparib using in vitro/ex vivo systems and animal models. Our results revealed that venadaparib has improved efficacy and safety; further investigation will be necessary in the clinical phase as an alternative class of PARP inhibitors in humans.

BRCA1 and BRCA2 are crucial for HR, and thus, it is expected that patients with a defective DNA damage repair system may also respond to PARP inhibitors (38). Although olaparib was approved for patients with HR repair gene-mutated metastatic castration-resistant prostate cancer, the clinical application is still limited mainly to patients with BRCA-mutated/platinum-sensitive cancers. A more potent PARP inhibitor with a tolerable safety profile is needed to overcome the restricted boundary of using PARP inhibitors. Our results showed that venadaparib, a novel and selective PARP inhibitor, has potent antitumor potency in multiple in vitro and in vivo models and a balanced trapping effect. Venadaparib also demonstrated favorable pharmacokinetic properties in the nonclinical studies. All these features indicate it is suitable for clinical trials. A phase I study evaluating the safety and tolerability of venadaparib in patients with advanced solid tumors (NCT03317743) has been completed. Therein, venadaparib showed a tolerable safety profile and a potential clinical benefit with a 1-day dosing schedule in patients with advanced solid tumors that progressed after standard-of-care therapy (39). Venadaparib is also being investigated in a Ib/IIa study in patients with HR repair genes–mutated solid tumors including patients previously treated with a PARP inhibitor (NCT4174716), and in those with advanced gastric cancer treated in combination with XELOX or irinotecan (NCT04725994). Hence, this study, highlighting the role of venadaparib as a PARP inhibitor, can further support the outcomes of these trials.

M. Lee reports grants from National-OncoVenture and personal fees from Ildong Pharmaceutical during the conduct of the study. I.-G. Je reports grants from National-OncoVenture during the conduct of the study. J.E. Kim reports grants from National-OncoVenture and personal fees from Ildong Pharmaceutical during the conduct of the study. Y. Yoo reports grants from National-OncoVenture during the conduct of the study. J.-H. Lim reports grants from National-OncoVenture, Grant during the conduct of the study. E. Jang reports grants from National-OncoVenture during the conduct of the study. Y. Lee reports personal fees from Ildong Pharmaceutical during the conduct of the study. D.K. Song reports personal fees from Ildong Pharmaceutical during the conduct of the study. A.-N. Moon reports personal fees from Ildong Pharmaceutical during the conduct of the study. J.-A. Kim reports personal fees from Ildong Pharmaceutical during the conduct of the study. J. Jeong reports grants from National-OncoVenture during the conduct of the study. J.-T. Park reports grants from National-OncoVenture during the conduct of the study. J.W. Lee reports grants from National-OncoVenture during the conduct of the study. J.-H. Yang reports grants from National-OncoVenture during the conduct of the study. C.-H. Hong reports grants from National-OncoVenture during the conduct of the study. S.-Y. Park reports grants from National-OncoVenture during the conduct of the study. N.-S. Baek reports grants from Ministry of Health and Welfare Korea during the conduct of the study. S. Lee reports grants from Ministry of Health and Welfare Korea during the conduct of the study. K.S. Ha is an employee of the Idience Inc. S. Choi reports grants from National-OncoVenture during the conduct of the study. W.S. Lee reports grants from National-OncoVenture during the conduct of the study. No disclosures were reported by the other author.

M. Lee: Conceptualization, writing–original draft, project administration. I.-G. Je: Formal analysis, investigation, visualization, methodology, writing–original draft. J.E. Kim: Formal analysis, validation, investigation. Y. Yoo: Formal analysis, investigation. J.-H. Lim: Formal analysis, investigation. E. Jang: Formal analysis, investigation. Y. Lee: Conceptualization. D.K. Song: Investigation. A.-N. Moon: Investigation. J.-A. Kim: Investigation. J. Jeong: Investigation. J.-T. Park: Resources, data curation, project administration. J.W. Lee: Data curation, project administration. J.-H. Yang: Investigation. C.-H. Hong: Investigation. S.-Y. Park: Investigation. Y.-W. Park: Funding acquisition. N.S. Baek: Funding acquisition, project administration. S. Lee: Funding acquisition. K.S. Ha: Writing–review and editing. S. Choi: Supervision. W.S. Lee: Supervision.

This study was conducted with the National-OncoVenture supported by the National Cancer Center, designated by the Ministry of Health and Welfare Korea (HI17C2196).

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