Source: FDA, National Drug Code (US) Revision Year: 2025
Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (ClpP). Dordaviprone also inhibits the dopamine D2 receptor.
Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In vitro, dordaviprone activated the integrated stress response, induced apoptosis, and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models.
Dordaviprone exhibited antitumor activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma.
At 1.2 times the maximum recommended dose, the estimated mean QTcF change was 11.8 msec (90% CI: 9.8, 13.7) [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of dordaviprone have not been fully characterized.
Dordaviprone pharmacokinetics were predicted following a single dose in patients at the approved recommended dosage and are presented as mean (CV%) unless otherwise specified. Dordaviprone maximum concentration (Cmax) is 2.8 mcg/mL (42%), and total systemic exposure (AUC) is 23 hr·mcg/mL (48%). Dordaviprone Cmax and AUC increased in a dose proportional manner over the dose range of 125 to 625 mg. No accumulation is observed following once weekly dosing.
Dordaviprone median (min, max) time to maximum plasma concentration (Tmax) is 1.4 hours (0.5, 5.6 hours).
Dordaviprone Cmax decreased by 40% with no change on AUC following administration with a high-fat meal (800 to 1,000 calories, 50% fat).
Dordaviprone apparent (oral) volume of distribution is 450 L (40%).
Dordaviprone plasma protein binding is 95% to 97% and independent of concentrations in vitro.
The median blood-to-plasma ratio is 0.67 in vitro.
Dordaviprone is primarily metabolized by CYP3A4 with minor contribution from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5.
Dordaviprone mean terminal half-life is 11 hours (30%), and the apparent clearance is approximately 27 L/hr (48%).
Following a single dose of radiolabeled dordaviprone, 70% of the dose was recovered in urine and 20% in feces with no notable unchanged dordaviprone in urine or feces.
No clinically significant differences in the pharmacokinetics of dordaviprone were observed based on age (3 to 90 years), sex, race (74% White, 9% Black or African American, or 5% Asian) or mild hepatic impairment (total bilirubin ≤ULN with AST >ULN or total bilirubin >1 to 1.5 times ULN with any AST).
The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on dordaviprone pharmacokinetics is unknown.
The exposure of dordaviprone in pediatrics weighing 10 kg and higher is predicted to be within the range of exposures predicted in adults at the recommended dosage.
Following a single oral dose of 375 mg (0.6 times the maximum approved recommended dose), dordaviprone AUC increased by 1.5-fold and Cmax by 1.1-fold in subjects with severe renal impairment (CLcr <30 mL/min, estimated by the Cockcroft-Gault equation).
Following a single oral dose of 125 mg (0.2 times the maximum approved recommended dose) dordaviprone AUC increased by 1.5-fold and Cmax by 1.2-fold in subjects with moderate hepatic impairment (Child Pugh class B).
CYP3A4 Inhibitors: Dordaviprone Cmax increased by 2-fold and AUC increased by 4-fold following concomitant administration of itraconazole (strong CYP3A4 inhibitor) 200 mg once daily for 8 days. Dordaviprone Cmax is predicted to increase by ~1.5-fold and AUC by 2.5-fold following concomitant administration of fluconazole or erythromycin (moderate CYP3A4 inhibitor).
CYP3A4 Inducers: Dordaviprone Cmax is predicted to decrease by 68% and AUC by 83% following concomitant administration of rifampin (strong CYP3A4 inducer) and dordaviprone Cmax is predicted to decrease by 44% and AUC by 65% following concomitant administration of efavirenz (moderate CYP3A4 inducer).
Other Drugs: No clinically significant difference in dordaviprone pharmacokinetics is predicted when used concomitantly with cimetidine (weak CYP3A4 inhibitor).
No clinically significant difference in dordaviprone pharmacokinetics is observed with multiple doses of a rabeprazole (proton-pump inhibitor).
No clinically significant differences in the pharmacokinetics of the following drugs are predicted following concomitant use with MODEYSO: dabigatran etixelate (P-gp substrate), rosuvastatin (BCRP substrate), midazolam (CYP3A substrate), desipramine (CYP2D6 substrate) and repaglinide (CYP2C8 substrate).
CYP Enzymes: Dordaviprone inhibits CYP1A2, CYP2B6, and CYP2C19 and induces CYP2B6.
Transporter Systems: Dordaviprone inhibits MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, and OCT1.
Carcinogenicity studies with dordaviprone were not conducted.
Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.
Dedicated fertility studies were not conducted with dordaviprone.
The nonclinical safety profile of dordaviprone reflects the on-target pharmacology and dopamine receptor inhibition. In repeat-dose toxicology studies of up 13 weeks in duration, weekly oral administration of dordaviprone to dogs caused central nervous system-related toxicities including whole body tremors, cranial tremors, seizures, excessive salivation, lateral recumbency, rigidity, paddling of limbs, overall rigid body, salivation, abnormal gait/stance, and twitching at doses resulting in less than or equal to 0.7 times the human exposure at the highest recommended dose based on AUC. In a 13-week repeat-dose toxicology study in rats, mammary gland hyperplasia occurred at doses resulting in 0.11 times the human exposure at the highest recommended dose based on AUC.
The efficacy of MODEYSO was evaluated in adult and pediatric patients with glioma across five open-label, non-randomized clinical studies conducted in the U.S. (ONC006 [NCT02525692], ONC013 [NCT03295396], ONC014 [NCT03416530], ONC016 [NCT05392374], and ONC018 [NCT03134131]). Pre-specified criteria were defined to establish an integrated efficacy population; eligible patients were required to have received single-agent MODEYSO, have diffuse midline glioma harboring an H3 K27M mutation with progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria, be ≥90 days post-radiation therapy, have adequate washout from prior anticancer therapies, have a Karnofsky Performance Status/Lansky Performance Status (KPS/LPS) score ≥60, and have stable or decreasing corticosteroid use. Patients with diffuse intrinsic pontine glioma (DIPG), primary spinal tumors, atypical histologies, or cerebrospinal fluid dissemination were excluded. Patients received weight-based dosing of MODEYSO until disease progression or unacceptable toxicity.
The integrated efficacy population included 50 patients who met these criteria. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent central review (BICR) according to RANO 2.0 criteria. Additional efficacy outcome measures were BICR-assessed ORR according to RANO-HGG criteria and Response Assessment in Neuro-Oncology-Low Grade Glioma (RANO-LGG) criteria, duration of response, and time to response.
Baseline demographics were: median age 31 years (range: 9 to 70) with 6% younger than 17 years of age; 46% female; 80% White, 6% Black or African American, 2% Asian, 10% other races, and 2% race unknown; 8% were of Hispanic or Latino ethnicity; 72% had KPS/LPS 80 to 100. Relevant disease characteristics included 72% treated at first recurrence, 28% had 2 or more recurrences; primary tumor location was thalamic in 52% and non-thalamic midline region in 48%; 88% received prior temozolomide; 62% were receiving corticosteroids at baseline; median time from end of prior radiation was 7.4 months (range: 3.0 to 102.1).
Efficacy results are shown in Table 8.
Table 8. Efficacy Results for Patients with Diffuse Midline Glioma Harboring an H3 K27M Mutation in Studies ONC006, ONC013, ONC014, ONC016, and ONC018 per RANO 2.0:
| Efficacy Parameter | MODEYSO N=50 |
|---|---|
| Overall Response Rate (95% CI)a | 22% (12, 36) |
| Partial response (PR) | 16% |
| Minor response (MR) | 6% |
| Duration of Response | N=11 |
| Median (95% CI)b, months | 10.3 (7.3, 15.2) |
| % with observed DOR ≥6 monthsc | 73% |
| % with observed DOR ≥12 monthsc | 27% |
Abbreviations: BICR=blinded independent central review; CI=confidence interval; RANO=Response Assessment in Neuro-Oncology.
a Confirmed overall response rate assessed by BICR; CI based on Clopper-Pearson method.
b Based on Kaplan-Meier estimate.
c Based on observed time.
Among responders, the median time to response was 3.6 months (range 1.6, 15.6).
Using BICR-assessed RANO 2.0 criteria, there was one additional responder based on the integrated response assessment, which takes into account corticosteroid use and performance status. Based on BICR-assessed RANO-HGG criteria (n=50), the ORR was 20% (95% CI: 10, 34), with 1 complete and 9 partial responses. Based on BICR-assessed RANO-LGG criteria (n=50), the ORR was 20% (95% CI: 10, 34), with 5 partial and 5 minor responses.
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