SOHONOS Capsule Ref.[107414] Active ingredients: Palovarotene

Cardiac Electrophysiology

At doses up to 2.5 times the maximum recommended dose, palovarotene does not prolong the QT interval to any clinically relevant extent.

Palovarotene exposure (AUC) increases proportionally from 0.02 to 50 mg (0.001 to 2.5 times the maximum recommended dosage). Steady-state is achieved by Day 3 following once daily dosing. Palovarotene exposure in patients with FOP are listed in the Table 7.

Table 7. Palovarotene Exposures in Patients with FOP:

Pharmacokinetics parameters are presented as mean (± SD).

Absorption

The median time to achieve peak concentration (T_max) of palovarotene was 3.0 to 4.0 hours across the chronic dose of 5 mg to flare-up dose of 10 and 20 mg.

Effect of Food

Palovarotene mean AUC and mean C_max increased by approximately 40% and 16%, respectively; T_max was delayed by approximately 2 hours with a high-fat, high-calorie meal (800 to 1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat).

No clinically significant differences in the AUC and C_max of palovarotene were observed when palovarotene was administered whole compared to the contents sprinkled onto one teaspoon of applesauce following a high-fat, high-caloric breakfast.

Distribution

The mean (SD) apparent volume of distribution (Vd/F) is 237 (± 90.1) L following administration of a single 20 mg dose with food. Protein binding of palovarotene is 97.9% to 99.6% in vitro.

The mean blood-to-plasma ratio of palovarotene in humans is 0.62.

Elimination

The mean elimination half-life is 8.7 hours following administration of a 20 mg once daily dosage for 14 days with a standard breakfast (800 to 1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat). The apparent total body clearance (CL/F) of palovarotene is estimated at 19.9 L/h.

Metabolism

Palovarotene is extensively metabolized by CYP3A4 and to a minor extent by CYP2C8 and CYP2C19.

Following administration of [¹⁴-C]-radiolabeled palovarotene, the contribution of palovarotene and its four known major metabolites (M2, M3, M4a, and M4b) represented collectively 40% of the total exposure in plasma. The pharmacological activity of M3 and M4b is approximately 1.7% and 4.2% of the activity of the parent drug.

Excretion

Following administration of a 1 mg dose of [¹⁴C]-radiolabeled palovarotene in healthy subjects, 97.1% of the dose was recovered in the feces and 3.2% in the urine.

Specific Populations

There were no clinically significant differences in the pharmacokinetics of palovarotene based on age (2 to 85 years old), sex, race (Asian, black, white and others), smoking status, mild to moderate renal impairment, or mild hepatic impairment. The effect of severe renal impairment, or moderate to severe hepatic impairment on the pharmacokinetics of palovarotene is unknown.

Body Weight

Body weight (13 to 130 kg) was found to have a significant effect on the pharmacokinetics of palovarotene resulting in increasing exposure with decreasing weight at the same dose.

Pediatric Patients

The estimated steady-state AUC_0-τ and C_max,ss following weight-based dosing for 5, 10, and 20 mg (or dose equivalent) in pediatric patients <14 years old are comparable for the equivalent doses across the different weight groups.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A Inhibitor: Co-administration of palovarotene with ketoconazole (strong CYP3A4 inhibitor) increased the C_max and AUC of palovarotene by 2 and 3-fold, respectively.

Moderate CYP3A Inhibitor: Co-administration of palovarotene with erythromycin (moderate CYP3A4 inhibitor) increased the C_max and AUC of palovarotene by 1.6 and 2.5-fold, respectively.

Strong CYP3A Inducer: Co-administration of palovarotene with rifampicin (strong CYP3A4 inducer) decrease the C_max and AUC_0-t of palovarotene by 19% and 11%, respectively.

Other Drugs: No clinically significant differences in the pharmacokinetics of palovarotene were observed when co-administered with prednisone 40 mg. No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with palovarotene.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Palovarotene is an inducer of CYP3A4 and CYP2B6, but not CYP1A2, CYP2C8, CYP2C9 and CYP2C19. Palovarotene is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Palovarotene is not an inhibitor or a substrate of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.

Transporter Systems: Palovarotene is not an inhibitor of P-gp, OAT1, OAT3, OCT2, MATE1, MATE2 K, BCRP, OATP1B1, OATP1B3, OCT1, and BSEP. Palovarotene is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, or OCT1.

Carcinogenesis and Mutagenesis

Long term studies to assess the carcinogenic potential of palovarotene have not been conducted.

Palovarotene and its metabolites were negative in the vitro bacterial reverse mutation (Ames) assay and an in vitro micronucleus assay in primary human lymphocyte. Palovarotene did not have any clastogenic effect in the in vivo mouse micronucleus study.

Impairment of Fertility

Palovarotene effects on fertility and reproductive function were assessed in male and female rats. In a female rat fertility study, palovarotene was orally administered to females for 14 days prior to mating with drug naïve males and up to GD 7 at the dose levels of 0.3, 1 and 3 mg/kg/day. Palovarotene caused prolonged periods of diestrous and reduced ovulation rate, resulting in lower numbers of implantation sites and live embryos at 3 mg/kg/day, a dose associated with maternal toxicity.

In a male rat fertility study, palovarotene was orally administered prior to mating, during mating, and up to scheduled euthanasia (approximately 11 weeks in total) at 0.3, 1 and 3 mg/kg/day. Palovarotene did not cause adverse effects on mating, fertility indices, conception rate, reproductive organ weights or sperm parameters up to 1 mg/kg/day (less than the clinical exposure). Males did not tolerate 3 mg/kg/day, as it produced severe systemic toxicity including deaths, adverse skin and hair coat clinical signs, and substantially reduced body weight.

14.1 Chronic/Flare-up Regimen

Study PVO-1A-301 (NCT03312634, Study 301) was a single arm study in 97 subjects with FOP with R206H mutation aged 4 years and older utilizing the Natural History Study (NHS, PVO-1A-001) as an external control (n=101). The primary efficacy endpoint was annualized volume of new heterotopic ossification (HO) as assessed by low-dose, whole body CT (WBCT) imaging (excluding head). All WBCT images from treated subjects in the 301 study and untreated subjects in the NHS were read in a manner blinded to study origination.

Study 301 subjects received SOHONOS 5 mg daily with increased dosing at the time of a flare-up defined as at least one symptom (e.g. pain, swelling, redness) consistent with a previous flare-up or a substantial high-risk traumatic event likely to lead to a flare-up, to 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks (denoted as the chronic/flare-up regimen), with flare-up treatment extension in 4-week increments for persistent symptoms. Anytime during flare-up treatment, the 12-week treatment restarted if the subject had another flare-up or substantial high-risk traumatic event. The dosing was adjusted according to body weight in skeletally immature children (children who had not reached at least 90% skeletal maturity defined as a bone age of ≥12 years 0 months for girls and ≥14 years 0 months for boys).

The mean age of subjects in the SOHONOS group (N=97) was 15.1 years; and 17.8 years in the untreated group (N=101). There were more male than female subjects in both the SOHONOS (53% and 47%, respectively) and untreated (55% and 45%, respectively) groups.

The mean annualized new HO was 9.4 cm³/year in subjects receiving the chronic/flare-up SOHONOS treatment and 20.3 cm³/year in untreated subjects in the NHS based on a linear mixed effect model. The treatment effect was about 10.9 cm³/year with 95% confidence interval (-21.2 cm³/year, -0.6 cm³/year).