Sonidegib Research Articles

Study on hydrolytic, oxidative and photolytic degradation behaviour of anticancer drug sonidegib: Characterization of the products by UHPLC-Q-TOF-MS/MS, 2D NMR and in silico toxicity assessment

Sonidegib (SDG) is a USFDA-approved anticancer drug developed for treating basal cell carcinoma. The presented study is focused on forced degradation studies of SDG with special emphasis on oxidative and photolytic degradation. Stress testing was performed as per ICH guidelines in hydrolytic, oxidative, and photolytic stress, revealing the formation of 15 transformation products. The results demonstrated the sensitivity of SDG to photolytic exposure under UV-A light, as well as to oxidative stress conditions involving hydrogen peroxide and a radical initiator. The observed DPs are separated and identified using RP-LC-PDA using a linear gradient program equipped with C18 (4.6 ×250 mm, 5 µm) column. All the DPs with >0.1 % concentration are characterized using tandem mass spectrometry and DPs with complex, unstable and isomeric nature are enriched and studied using solution NMR. Enrichment studies unveiled the formation of DP-6, DP-11, DP-12 and DP-13 as major transformation products. Interpretation of characteristic fragments from MS/MS spectra, NMR chemical shifts, and NOEs are utilized to solve the structure of the DPs. Further elucidated structures are employed to propose the involved mechanisms in degradation pathway. In addition, the DPs are studied for toxicity in silico and the potential/plausible carcinogenic, genotoxic and mutagenic nature of the DPs are illustrated.

Comparison of Three Antagonists of Hedgehog Pathway to Promote Skeletal Muscle Regeneration after High Dose Irradiation.

The current geopolitical context has brought the radiological nuclear risk to the forefront of concerns. High-dose localized radiation exposure leads to the development of a musculocutaneous radiation syndrome affecting the skin and subcutaneous muscles. Despite the implementation of a gold standard treatment based on an invasive surgical procedure coupled with autologous cell therapy, a muscular defect frequently persists. Targeting the modulation of the Hedgehog (Hh) signaling pathway appears to be a promising therapeutic approach. Activation of this pathway enhances cell survival and promotes proliferation after irradiation, while inhibition by Cyclopamine facilitates differentiation. In this study, we compared the effects of three antagonists of Hh, Cyclopamine (CA), Vismodegib (VDG) and Sonidegib (SDG) on differentiation. A stable cell line of murine myoblasts, C2C12, was exposed to X-ray radiation (5 Gy) and treated with CA, VDG or SDG. Analysis of proliferation, survival (apoptosis), morphology, myogenesis genes expression and proteins production were performed. According to the results, VDG does not have a significant impact on C2C12 cells. SDG increases the expression/production of differentiation markers to a similar extent as CA, while morphologically, SDG proves to be more effective than CA. To conclude, SDG can be used in the same way as CA but already has a marketing authorization with an indication against basal cell cancers, facilitating their use invivo. This proof of concept demonstrates that SDG represents a promising alternative to CA to promotes differentiation of murine myoblasts. Future studies on isolated and cultured satellite cells and invivo will test this proof of concept.

Analytical quality by design aided stability indicating a robust ultra‐performance liquid chromatographic technique for the quantification of sonidegib and its organic impurities in bulk drug substance

AbstractA simple quality by design aided stability indicating method was developed for quantification of sonidegib (SONI) and its process related impurities using on ultra‐performance liquid chromatography in bulk drug substance. AutoChrom and Design‐Expert software were used to predict physicochemical properties, draw Ionization graphs, and generate analytical target profile. SONI was subjected to forced degradation conditions, such as oxidative, acid hydrolysis, base hydrolysis, hydrolytic, thermal, and photolytic hydrolysis. All degradation products and process contaminants were separated using an Acquity Ethylene Bridged Hybrid C18 column in gradient elution mode with a mobile phase containing 0.02 M ammonium acetate buffer and acetonitrile: methanol (80:20 v/v). The predicted physicochemical properties are accurate and they facilitated for selection of robust conditions in development of chromatographic method with minimal trials. The developed method can be used for quantification of drug and its process related impurities in bulk drugs.

Analytical and bioanalytical HPLC method for simultaneous estimation of 5-fluorouracil and sonidegib.

Aim: To develop a new sensitive RP-HPLC method for simultaneous estimation of 5-fluorouracil (5-FU) and sonidegib (SDG). Materials & methods: Analytical and bioanalytical methods for simultaneous quantification of 5-FU and SDG in bulk, nanoformulations and in rat plasma were developed and validated using a gradient elution technique. Results: Separation of the analytes was effected on a Luna® C18 LC column using a mobile mixture comprising acetonitrile and acidified water. 5-FU and SDG were extracted from plasma matrix using liquid-liquid extraction. The applicability of the method was verified through single-dose oral pharmacokinetic study in Wistar rats. Conclusion: The developed methods allow a specific, sensitive and steady analytical procedure for the simultaneous estimation of 5-FU and SDG in nanoformulations and biological matrix.

Improving the Antitumor Activity and Bioavailability of Sonidegib for the Treatment of Skin Cancer.

Throughout the United States and the world, skin cancer is the most frequent form of cancer. Sonidegib (SNG) is a hedgehog inhibitor that has been used for skin cancer treatment. However, SNG has low bioavailability and is associated with resistance. The focus of this work is to enhance bioavailability, anti-tumor efficacy and targeting of SNG via developing ethosome gel as a potential treatment for skin cancer. SNG-loaded ethosomes formulation was prepared and characterized in vitro by %entrapment efficiency (%EE), vesicle size, morphology, %release and steady-state flux. The results showed that the prepared formulation was spherical nanovesicles with a %EE of 85.4 ± 0.57%, a particle size of 199.53 ± 4.51 nm and a steady-state flux of 5.58 ± 0.08 µg/cm2/h. In addition, SNG-loaded ethosomes formulation was incorporated into carbopol gel to study the anti-tumor efficacy, localization and bioavailability in vivo. Compared with oral SNG, the formulation showed 3.18 times higher relative bioavailability and consequently significant anti-tumor activity. In addition, this formulation showed a higher rate of SNG penetration in the skin’s deep layers and passive targeting in tumor cells. Briefly, SNG-loaded ethosome gel can produce desirable therapeutic benefits for treatment of skin cancer.

Phase I/IB Study of Azacitidine and Hedgehog Pathway Inhibition with Sonidegib (LDE225) in Myeloid Malignancies

Background: Lower intensity therapies for patients (pts) with myeloid malignancies (AML, MDS, CMML, MPNs) are beneficial, but suboptimal despite the emergence of potentially active new agents. Even after an initial response to hypomethylating agents (HMAs) [5-Azacitidine (AZA) or decitabine], the majority of patients fail treatment. In large-scale RNAi screens we identified Hedgehog pathway (HP) genes as a potential rational combination to overcome a priori and acquired HMA resistance. Herein we report the first analysis of the final study results of the oral smoothened (SMO) inhibitor, Sonidegib (LDE225) in combination with AZA in 63 pts treated on a Phase 1/1B (Ph1/1B) trial.Methods: Ph1 (3+3) dose escalation and Ph1B (expansion cohort) study to determine the MTD (Ph1) and best overall response (Ph1B) of Sonidegib (SON) combined with AZA. 2nd endpoints included AEs, DOR, TTP, OS, time to AML for MDS pts and QOL. Pts with untreated and relapsed/refractory (rel/ref) AML, CMML, MDS, MDS/MPN overlap (MDS/MPN) or myelofibrosis (MF) were eligible. SON was started at dose level (DL) 0 at 400mg oral daily continuously (28 day cycle) and AZA at 75mg/m2 x 7 days or days 5-2-2 with dose adjustment per label. Dose-limiting toxicity (DLT) in Ph1 was assessed after 42 days at steady-state concentrations of SON. Pharmacokinetics were not performed.Results:Study population:From 05/2014 to 05/2017 (data cut-off) 63 pts were enrolled and followed for outcome: 10 pts were treated on the Ph1 and 52 in Ph1B part of the trial (1 pt withdrew). Median age was 72.5 years (range 39-86) and 66% pts were male. ECOG 0, 1 and 2 are 34%, 61% and 5% respectively. 45% (n=28) were newly diagnosed and 55% (n=34) rel/ref pts. 38 pts (61%) had AML and 13 of the 15 newly diagnosed/untreated AML pts had 2nd AML due to AHD; 23/38 pts had rel/ref AML. For all AML pts 21/38 were intermediate risk and 16/38 had unfavorable cytogenetics (1/38 unknown). 18 pts (29%) had MDS, all in the Intermediate, High or Very High risk status (IPSS-R), 4 (6.5%) had CMML and 2 pts MF.Dose levels, treatment administration and follow up: 6 pts were treated at DL0 SON 400mg/day continuously with AZA and 1 DLT of CPK elevation observed, while another pt had grade 4 neutropenia (at that time included in DLT definition, later removed). Due to overall tolerance of the combination at DL0 and investigator assessment, despite only 1/6 formal DLTs, DL -1 at SON 200mg x28 days was explored without further DLT (n=4 pts) and 52 pts accrued on Ph1B. For the 56 pts treated at the MTD dose of SON 200mg (Ph1B=52 and Ph1=4 pts), after a median of 14.5 months follow up, 218 cycles have been administered (median 3 cycles-range 1-25 ms). Median doses for SON and AZA were 200mg and 75mg/m2 respectively. 12.5% and 18% of pts had dose adjustments and 71.4% (i.e. missed only 1 dose) and 18% dose omissions at least once for SON and AZA respectively. 19/56 (34%) of pts are alive.Safety and Tolerability : Of 56 pts treated at MTD dose100% experienced at least one grade (gr) 3 AE and 52 (93%) had a gr 4 AE regardless of attribution. 96% and 91% had a gr 3 and gr 4 Heme AE and 73% and 20% had a gr 3 and gr 4 Non-Hem AE respectively. Gr 3/4 AEs were as expected for either drug and the diseases under study and were: thrombocytopenia (n=51), neutropenia (47), anemia (43), leukopenia (41). Most common gr 1/2 AEs were: fatigue (n=48), constipation (29), nausea/cough (each 24), insomnia (19), diarrhea (18), abdominal pain (16). 4/56 pts died on study deemed not drug related (cardiac arrest, MOF, neoplasm, sudden death).Efficacy: With a median follow up of 14.5 ms the best response outcome for untreated AML/MDS patients was 23.1% and for rel/ref 7.1%. However, the rate of SD (NR) was remarkably high particularly in the rel/ref AML population at 76% (16/21 pts, 2 not yet assessed). This high disease control rate was reflected in an OS of 7.6 ms (4.6-NE) in rel/ref AML, the majority of which failed previous HMAs .Conclusion: In this, to date largest SMO inhibitor/HMA combination trial, the oral SMO inhibitor SON was safe with full dose AZA in untreated and previously treated AML, MDS/CMML and MF pts. Although remission rates are not superior to single agent AZA in the heavily pre-treated and advanced myeloid malignancy population, the OS and lack of progression are encouraging, particular in the rel/ ref AML population indicating that SMO/Hh pathway inhibition may add to HMA efficacy. Predictive biomarker studies are ongoing. DisclosuresMesa:Ariad: Consultancy; Galena Biopharma, Inc.: Consultancy; CTI BioPharma Corp.: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Promedico: Research Funding; Gilead Sciences, Inc.: Research Funding; Celgene Corporation: Research Funding.