Mechanism of Action

Sonidegib (Odomzo^®) is an inhibitor of SMO, a transmembrane protein involved in Hedgehog signal transduction.

Signal transduction by activated SMO leads to the activation and nuclear localization of Gli1 transcription factors and induction of Hedgehog target genes involving in cell proliferation, cell survival and angiogenesis.

Sonidegib showed an IC₅₀ of 11 nM in an agonist displacement assay using human Smo.

Sonidegib showed an off-target activity across a panel of 150 G-protein coupled receptors, transporters, ion channels, nuclear receptors and enzymes.  Activities of 50% inhibition were found in 4 assays at 10 μM: Human melatonin MT1 receptor (IC₅₀ = 1.1 μM), human cannabinoid CB2 receptor (IC₅₀ = 9.7 μM), rat brain sodium channel type II (IC₅₀ = 0.82 μM) and rabbit vesicular monoamine transporter VMAT (IC₅₀ = 10 μM).

In Vitro Efficacy

Inhibition of sonidegib on HH-N protein inducted Gli-1 expression: IC₅₀ = 12.7 nM.

Sonidegib diminishe cell viability:

●    Ovarian cancer cells: IC₅₀ = 7.5-24 nM.

●    Melanoma cells: IC₅₀ = 81.38-139.3 nM.

●    Patched mutant mice cell: IC₅₀ = 9.3 nM.

Sonidegib inhibits Hedgehog gene expression in A2780cp20:

●    Ptch1: %Inhibition = 39%.

●    GLI1: %Inhibition = 43%.

●    GLI2: %Inhibition = 39%.

Sonidegib induced G1 cell cycle arrest and apoptosis in human melanoma cell lines:

●    Lox IMVI: Cell cycle arrested in G1 phase and induced apoptosis at 10 μM.

●    UACC257: Cell cycle arrested in G1 phase and induced apoptosis at 10 μM.

The effect of sondegib on ex vivo cultures of skin punch biopsies from 17.5 day Ptch^+/- LacZ mouse embryos:

●    Both Hh signalling and basaloid nests formation were dose-dependently inhibited by Sonidegib and Hh-Antag691.

In Vivo Efficacy

Sonidegib inhibited hair growth in mice models:

●    C57BL/6 mouse model: Sonidegib delayed hair growth.

●    The effects of Sonidegib on Hedgehog signaling gene expression in C57BL/6 mice: 1.0% cyclopamine with results similar to 0.1% Sonidegib phosphate on inhibition of hair growth; 1.0% sonidegib inhibited the expression of Gli1, Gli2 and Sox9.

●    C57BL7/6 mice depilation model: Sonidegib effectively blocked anagen entrance when given 3 days after depilation.

●    A375 xenograft NOG mouse model: Decreased tumor volume.  Ptch1 expression was 60% lower in the tumors.   

●    LOX IMVI xenograft mice model: Significant antitumor response.  Decreased GLI1 expression.

●    MDA-MB-231 xenograft mice model: Significant reduced tumor growth.

Absorption of Sonidegib

Exhibited dose-proportional increases in AUC and C_max over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg.  In humans, AUC_inf and C_max of sonidegib were approximately 7 time higher when administrated after a high-fat meal compared to fasted subjects.

Had a high oral bioavailability in rats (78%) and a moderate oral bioavailability in dogs (37.9%).

Was rapidly absorbed with T_max of 2 h in humans and slowly in rats (4 h) and dogs (8 h).

The half-life of sonidegib in humans (190-240 h) was long after oral administration.

The system clearance of sonidegib in dogs (0.476 L/h/kg) and in humans (45-75 L/h) were moderate among 20% to 80% of cliver blood flow.

The volume of distribution in dogs (10.8 L/kg) after intravenous administration, in rats (4.8 L/kg) and humans (1200-2000 L) after oral administration were higher than body water, suggesting sonidegib had an extensive distribution in tissues.

Showed moderate permeability of 4.58 ×10^-6 cm/s in Caco-2 cell monolayer model.

Distribution of Sonidegib

Exhibited high plasma protein binding in mice, rats, dogs, minipigs and humans (97-99%).  The binding was independent of concentration in all five species.  The C_b:C_p was less than 1, suggesting sonigegib predominantly distributed into plasma.

Long Evans Hooded (LEH) Rats and in Hanover Wistar (HW) rats following oral administration:

●    Sonidegib was widely distributed to most tissues in rat, and crossed the blood-brain barrier due to radioactivity concentrations in brain and spinal cord were observed though 7-day postdose.

●    The highest tissue distribution was observed in the uveal tract, followed by the harderian gland, fat, liver, small intestine, adrenal cortex, and adrenal medulla.

●    Drug derived radioactivity was associated with the melanin-containing tissues in the eye and pigmented skin.  Uptake into melanin-rich tissues was found to be at least partially reversible.  Therefore, corneal disorders had been included as important potential risks.

Metabolism of Sonidegib

Sonidegib undergoes extensive metabolism with some involvement of CYP3A4. The predominant metabolites in hu-man liver microsomes (HLM) were M50, M51, M53, and M25. ^[5]

CYP3A4 (at least 29% of its overall metabolism) and CYP3A5 were capable of metabolizing sonidegib.  In vitro studies indicated that CYP3A4 was responsible for the formation of M16 (LNC119), M23 (LMT323), M26 (LMR550), M33.2, and M48 (LGE899). ^[5]

The predominant component was parent and the major metabolite was M448 (LGE899) in human plasma.  After oral administration of [¹⁴C] sonidegib in rats and dogs, the AUC for sonidegib was <1% of the total radioactivity exposure, with M48 (LGE899) contributing >95% of the exposure.

No unique metabolites were identified in human plasma.  17 metabolites, amounting for 88.9% of the total radioactivity, were identified in human plasma.  Oxidations and oxidative cleavages (N/O dealkylation) in the morpholine ring appeared to be major metabolic pathways of sonidegib in all species.

The pharmacologic activity M25 (LMT326), M16 (LNC119) and M23 (LMV128) would not contribute to the observed efficacy due to the low concentrations in plasma. ^[4,10]

Excretion of Sonidegib

The predominant elimination route of sonidegib was via feces in rats, dogs, and humans, and the major component was parent in feces in these species, the major component was M47e in human urine.

Drug-Drug Interaction

Sonidegib inhibited potently CYP2B6 (IC₅₀ = 0.007 µM) and CYP2C9 (IC₅₀ = 0.237 µM), but not an inhibitor of other major CYP450 enzymes.

Sonidegib had no induction for CYP450 enzymes.

Sonidegib inhibited BCRP (IC₅₀ = 1.5 µM), but was not a substrate of BCRP.

Sonidegib was not a substrate and inhibitor of other transporters.

Single Dose Toxicity

Single-dose toxicity studies with sonidegib were conducted in rats: The maximum non-lethal dose (MNLD) was ≥2000 mg/kg.

Repeated Dose Toxicity

Repeated-dose toxicity studies were conducted by oral administration of sonidegib for up to 26 weeks in rats and dogs:

●    The main target organs of toxicity in both species included the teeth, skin, bone, and GI tract.

●    Skin toxicity consisted of alopecia with histopathological atrophy of hair follicles.

●    Bone toxicity consisted of thinning/closure of the growth plate in various bones.

●    Teeth abnormalities included missing or fractured teeth and histopathological atrophy.

●    Additional sonidegib-induced toxicity in both species consisted of uterus atrophy, increased cholesterol levels and increased creatinine kinase.

Safety Pharmacology

Both in vitro and in vivo safety pharmacology studies were conducted to assess the effects of sonidegib on neurological, cardiovascular, and respiratory system.

●    Sonidegib was a weak hERG blocker with a low potential to induce QT prolongation.

●    There was no toxicologically significant adverse effects on cardiovascular, neurological, or respiratory function.

Genotoxicity

Sonidegib was not mutagenic in the in vitro Ames assay.

Sonidegib was not clastogenic in the in vitro chromosomal aberration assays in mammalian cells, or in vivo rat bone marrow micronucleus assay.

Reproductive and Developmental Toxicity

Fertility and early embryonic development in rats

●    At doses ≥20 mg/kg/day: A lack of fertility in females and no adverse effects in males.

●    At 2 mg/kg/day: Reduction in the number of pregnant females, increase in the number of early resorptions, and decrease in the number of viable fetuses.

Embryo-fetal developmental in rabbits

●    At doses ≥2 mg/kg/day in pregnant rabbits: Abortion, complete resorption of fetuses, or severe malformations.

●    Teratogenic effects included vertebral, distal limb, digit, severe craniofacial malformations, and other severe midline defect.

●    Skeletal variations were observed when maternal exposure to sonidegib was below the limit of detection.

Juvenile in rats for 5 weeks

●    At doses ≥10 mg/kg/day: Sonidegib-induced toxicity included the bones, teeth, reproductive tissues, and nerves.

●    Bone toxicity included thinning/closure of bone growth plate, decreased bone length and width, and hyperostosis.

●    Reproductive tissue toxicity included atrophy of testes, ovaries, and uterus, partial development of the prostate gland and seminal vesicles, inflammation and aspermia of the epididymis.

Carcinogenicity

Carcinogenicity studies with sonidegib have not been conducted.