Sonidegib: First Global Approval
Celeste B. Burness1 © Springer International Publishing Switzerland 2015
Abstract
Sonidegib (OdomzoTM) is an orally bioavail- able, small molecule, Smoothened (SMO) receptor antag- onist that is being developed by Novartis for the treatment of cancer. SMO is a G protein-coupled receptor-like molecule that is essential for the actions of the Hedgehog family of secreted proteins, which play a critical role in the development and homeostasis of many organs and tissues. Oral sonidegib is approved in Switzerland for the treatment of adult patients with advanced basal cell carcinoma (BCC) and in the US and EU for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candi- dates for surgery or radiation therapy. Submissions to other global authorities are being contemplated or planned. Additionally, phase I/II investigation is being conducted in other malignancies, including multiple myeloma, medul- loblastoma, myelofibrosis, ovarian cancer, prostate cancer,breast cancer, chronic myeloid leukaemia, myelodysplastic syndromes, oesophageal cancer and pancreatic cancer. This article summarizes the milestones in the development of sonidegib leading to the first approvals for advanced and locally advanced BCC.
1 Introduction
The Hedgehog (Hh) signalling pathway is a developmental pathway involved in numerous processes, including deter- mination of cell fate, patterning, proliferation, survival and differentiation [1]. While this pathway is usually silenced in most adult tissues, aberrant activation of the Hh sig- naling pathway has been implicated in the pathogenesis of several types of cancer such as basal cell carcinoma (BCC) [2]. The Hh pathway can be stimulated by three Hh ligands: Sonic-Hh, Indian Hh and Desert-Hh, with Sonic- Hh being most extensively studied [1]. When these ligands bind to Patched (PTCH), a protein that acts as a repressor of the pathway, the inhibition of Smoothened (SMO) by PTCH is alleviated [1]. Activated SMO subsequently ini- tiates a downstream signalling cascade leading both to the activation of transcription factors belonging to the Glioma- associated oncogene (GLI) family and to the transcription of GLI target genes [1]. Therefore, recent research has focused on developing new therapeutic strategies to inter- rupt the Hh signaling pathway [1]. One such strategy is to block the SMO receptor, an essential component of the canonical Hh signaling pathway [1, 3]. Sonidegib (OdomzoTM) is an orally bioavailable, small molecule, SMO receptor antagonist that is being developed by Novartis for the treatment of various types of cancer [4].
Oral sonidegib received its first global approval in Switzerland on 30 June 2015 for the treatment of adult patients with advanced BCC who are not amenable to curative surgery or radiation therapy [5]. In July 2015, the US FDA approved oral sonidegib capsules for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy [6]. The approval was based on results from the phase II, randomized, BOLT trial (NCT01327053) [6, 7]. Additionally, sonidegib has been approved in the EU for the treatment of adult patients with locally advanced BCC who are not amenable to curative surgery or radiation therapy [8]. The recommended dosage of sonidegib is 200 mg once daily taken on an empty stom- ach, at least 1 h before or 2 h after a meal [4].
The US approval carries a black box warning regarding the potential of the drug to cause embryo-fetal death or severe birth defects when administered to a pregnant woman and is embryotoxic, fetotoxic and teratogenic in animals [4]. Pregnancy status should be verified prior to the start of treatment, and both male and female patients should be warned about these risks and advised to use effective contraception [4].
Submissions to other global authorities for the use of sonidegib for the treatment of locally advanced BCC are being contemplated or planned. Phase I–II development is underway in several other countries for various other malignancies. Clinical studies also evaluated the efficacy and tolerability of a topical formulation of sonidegib in patients with basal cell nevus syndrome [9]; however, its development in this indication was later discontinued.
2 Scientific Summary
2.1 Pharmacodynamics
Sonidegib binds to and inhibits SMO, a transmembrane protein involved in Hh signal transduction [4].Sonidegib has demonstrated inhibition of Hh signaling and antitumour activity in vitro, and in various in ani- mal models of cancer [10–18]. For instance, sonidegib inhibited cell viability, neurosphere formation, and GLI transcriptional activity and induced apoptosis by acti- vation of caspase-3 and cleavage of poly (ADP-ribose) polymerase in vitro [10, 12]. Additionally, sonidegib significantly reduced tumour volume by 95 % compared with untreated mice in a transgenic mouse model of islet cell neoplasms [15].
In patients with BCC, characteristic features of BCC on high-resolution skin imaging techniques decreased or dis- appeared completely during treatment with sonidegib [19]. For instance, imaging revealed a loss of the peripheral rim surrounding the tumour nodules, loss of peripheral pal- isading of tumour cells, blurry demarcation of the residual nodules and an increase in fibrotic tissue [19].
Sonidegib exhibits dose- and exposure-dependent inhi- bition of GLI homolog 1 (GLI1) in tumour and normal skin biopsies [20]. In tumour samples from patients with advanced BCC, sonidegib 200 or 800 mg once daily sig- nificantly reduced GLI1 levels from baseline after 9 and 17 weeks (p \ 0.0001) [21].
The QTc interval was not prolonged during treatment with sonidegib 800 mg once daily [4].
2.2 Pharmacokinetics
Following the administration of a single sonidegib dose (100–3000 mg) under fasted conditions in patients with can- cer, oral sonidegib was rapidly absorbed, with peak concen- trations reached within 2–4 h [4, 20]. Following a dose of 200 mg once daily, the estimated mean steady-state peak concentration was 1030 ng/mL, area under the concentration time curve (AUC0–24h) was 22 lg·h/mL and minimal con- centration was 890 ng/mL [4]. The absolute bioavailability of sonidegib was low (estimated to be 6–7 %) in volunteers after 800 mg [22]. Sonidegib exposure was increased by 7.4- to 7.8- fold following coadministration with a high-fat meal (ap- proximately 1000 calories with 50 % of calories from fat) [4]. Sonidegib exposure was approximately dose proportional up to 400 mg and less than dose proportional at higher doses ([400 mg), likely because of solubility-limited absorption [4, 20]. Twice-daily dosing resulted in higher systemic exposures compared with the equivalent once-daily regimen [20]. Steady-state was reached approximately 4 months after starting sonidegib and the estimated accumulation at steady- state was 19-fold [4, 20].
Absorbed sonidegib was distributed extensively into the tissues [22]. The estimated apparent steady-state volume of distribution was 9166 L [4]. Sonidegib was highly bound to human plasma proteins in vitro ([97 %) and the binding was concentration independent [4]. In vitro studies suggest sonidegib is not a substrate of ABCB1 (P-glycoprotein), ABCC2 (MRP2, cMOAT) or ABCG2 (BCRP) [4].
Sonidegib is metabolized primarily via oxidation and amide hydrolysis [4, 22]. The cytochrome P450 (CYP) enzyme CYP3A4 is predominant in the metabolism of sonidegib [4, 23]. The main circulating compound was unchanged sonidegib (36 % of circulating radioactivity) [4, 22]. The elimination of absorbed sonidegib occurred pre- dominantly or exclusively by metabolism in the liver [4,22]. Of the absorbed dose, approximately 70 % was eliminated in the feces and 30 % was eliminated in the urine [4]. No unchanged sonidegib was detected in urine [4, 22]. According to population pharmacokinetic model- ing, the mean elimination half-life of sonidegib was &28 days [4].
Features and properties of sonidegib
Gender, age, bodyweight, mild or moderate renal impairment and mild hepatic impairment had no clinically important effects on the exposure to sonidegib, according to a population pharmacokinetic analysis [4].
2.2.1 Drug Interactions
Pharmacokinetic drug interactions are possible when sonidegib is administered with strong inhibitors of CYP3A4 (e.g. saquinavir, telithromycin or ketoconazole) and with moderate inhibitors CYP3A4 (e.g. atazanavir, diltiazem or fluconazole) [4, 23]. The plasma exposure to sonidegib increases when sonidegib was coadministered with a strong (ketoconazole) or moderate (erythromycin) CYP3A4 inhibitor. On this basis, coadministration of sonidegib with strong or moderate CYP3A inhibitors should be avoided. If coadministration of sonidegib with a moderate CYP3A inhibitor is required, only administer the moderate CYP3A inhibitor for \14 days and monitor closely for adverse reactions (particularly musculoskeletal adverse events) [4].
Coadministration of sonidegib with strong and moderate CYP3A inducers [e.g. phenytoin, rifampin (rifampicin), St John’s Wort] may decrease the plasma exposure to soni- degib; consequently, concomitant use of sonidegib with these agents should also be avoided [4].
Sonidegib coadministered with a proton pump inhibitor or a histamine-2-receptor antagonist decreased the geo- metric mean sonidegib steady-state AUC0–24h by 34 %, based on population pharmacokinetic analysis [4].
2.3 Therapeutic Trials
2.3.1 Basal Cell Carcinoma
Oral sonidegib was effective in patients with locally advanced or metastatic BCC in the multicentre, double- blind, phase II BOLT trial (NCT01327053) [7]. BOLT included patients aged C18 years with locally advanced BCC not amenable to curative surgery or radiation (n = 194) or metastatic BCC (n = 36). Patients were randomized to once-daily oral sonidegib 200 (n = 79) or 800 mg (n = 151) on a continuous dosing schedule. The primary endpoint was objective response rate, which is the percentage of patients who experienced partial shrinkage or complete disappearance of their tumour(s) with data col- lected up to 6 months after randomization of the last patient. The median follow-up was 13.9 months [7].
In the primary efficacy analysis population (patients with fully assessable locally advanced BCC and all patients with metastatic BCC), objective response rates, as determined by blinded central review, were 36 % (95 % 24–50) and 34 % (95 % 25–43) in the sonidegib 200 and 800 mg once daily groups, respectively [7]. More specifically, 43 % of patients with locally advanced disease and 15 % of patients with metastatic disease, in the sonidegib 200 mg once daily group, and 38 % of patients with locally advanced disease and 17 % of patients with metastatic disease in the sonidegib 800 mg once daily group, achieved an objective response [7].
The median duration of response (DoR) in patients with metastatic disease receiving sonidegib 800 mg once daily was 8.3 months [7]. DoR could not be estimated for the other groups, as the majority of patients who had a response had had no event at the time of the analysis (event defined as progression or death due to any cause). The median progression-free survival (PFS) per central review for patients with metastatic disease was 13.1 months and 7.6 months in the 200 and 800 mg once daily groups, respectively. Median PFS could not be reached for patients with locally advanced disease, since the majority had had no event at the time of analysis. The median time to tumour response (TTR) per central review for patients with locally advanced disease was 3.9 months and 3.7 months in the 200 and 800 mg once daily groups, respectively. In patients with metastatic disease, median TTR was 4.6 months and 1.0 month in the 200 and 800 mg once daily groups, respectively. In patients with locally advanced disease, disease control was achieved in 93 and 80 % of patients receiving sonidegib 200 and 800 mg once daily, respectively. The corresponding proportions of patients achieving disease control in patients with meta- static disease were 92 and 83 % [7].
2.3.2 Medulloblastoma
Preliminary data from a phase I/II trial (NCT01125800) suggest that sonidegib was effective in patients with Hh- activated relapsed/refractory medulloblastoma, or other tumours potentially dependent on Hh signalling, such as rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high grade glioma or osteosarcoma [24]. In the phase I dose escalation portion of the trial, 59 children (38 with medulloblastoma), aged 2–17 (median 12) years, were treated with sonidegib starting at 372 mg2; the recom- mended phase II dose was established as 680 mg/m2 once daily for children and adolescents. In the phase II portion, patients with relapsed/refractory medulloblastoma, includ- ing 12 adult patients, were treated at previously established recommended clinical doses of sonidegib (800 mg once daily in adults and 680 mg/m2 in children). Among patients with medulloblastoma treated in both phases of the study (n = 50), three patients had complete responses while receiving once-daily sonidegib 372 mg/m2, 425 mg/m2 or 800 mg/day and one patient had a partial response while receiving sonidegib 800 mg once daily. Subsequently, these patients were found to have Hh-activated tumours (analyzed using a RT-PCR-based five-gene Hh signature assay). One adult and one pediatric patient with Hh-acti- vated tumours had stable and progressive disease, respec- tively. No responses were observed in the patients who were determined to have tumours not activated by the Hh pathway [24].
2.3.3 Myelofibrosis
Sonidegib in combination with ruxolitinib appears to be effective in patients with myelofibrosis according to the results of an ongoing phase Ib/II trial (NCT01787552) [25]. Patients (median age 67 years) with primary or secondary (post–polycythemia vera or post-essential thrombo- cythemia) intermediate- or high-risk myelofibrosis with palpable splenomegaly not previously treated with Janus kinase inhibitors or SMO inhibitors received sonidegib 400 mg once daily plus ruxolitinib 10 mg twice daily (n = 8), sonidegib 400 mg once daily plus ruxolitinib 15 mg twice daily (n = 10) or sonidegib 400 mg once daily plus ruxolitinib 20 mg twice daily (n = 5). At data cutoff, 65 % of patients achieved a C50 % reduction in palpable spleen length from baseline and nine patients had resolution of splenomegaly [25].
2.3.4 Small-Cell Lung Cancer
In an ongoing phase I trial (NCT01579929) in patients with extensive stage small-cell lung cancer receiving etoposide and cisplatin, oral sonidegib was associated with a partial response in 50 % of patients (7/14 patients) [26]. Sonidegib 800 mg once daily was determined as the recommended phase II dose when administered with etoposide and cis- platin. In this open-label study, newly diagnosed patients with extensive small-cell lung cancer (median age 56 years), Karnofsky performance status C70 and asymp- tomatic brain metastases received sonidegib 200 mg once daily (n = 2); 400 mg once daily (n = 7); 800 mg once daily (n = 5) as capsules. Treatment was continued until disease progression or unacceptable toxicity. The first 3 patients were enrolled at 400 mg once daily, and two experienced a dose limiting toxicity, leading to dose de- escalation (200 once daily). Three patients received maintenance sonidegib for C4 months [26].
2.3.5 Chronic Myeloid Leukaemia
A phase Ib trial (NCT01456676) in patients with in patients with Philadelphia chromosome positive chronic myeloid leukaemia in chronic phase refractory/intolerant to at least 1 prior tyrosine kinase inhibitor (n = 11) demonstrated that the benefits of adding sonidegib to nilotinib did not out- weigh the additional risks [27]. The study was terminated early due to lack of efficacy [27].
2.4 Adverse Events
Sonidegib was generally well tolerated in patients with locally advanced or metastatic BCC [4, 7]. In the ran- domised phase II BOLT trial, grade 3 or 4 adverse events occurred less frequently in the 200 mg once daily dose group (30 %) than in the 800 mg once daily group (56 %) [7]. Grade 3 or 4 adverse events occurring in C2 % of patients in the 200 mg once daily group were elevated creatine phosphokinase (6 %), increased lipase (5 %), and hypertension, asthenia and muscle spasms (all 3 %). Grade 3 or 4 adverse events reported by C2% of patients in the 800 mg once daily group were elevated creatine phos- phokinase (13 %), increased lipase, muscle spasms and weight loss (all 5 %), decreased appetite (4 %), rhab- domyolysis, nausea, hypertension, increased alanine aminotransferase and increased aspartate aminotransferase (all 3 %), and fatigue, syncope, anaemia, dehydration, hyperkalaemia and myalgia (all 2 %); none of the cases of rhabdomyolysis reported by investigators was confirmed by the independent safety review and adjudication com- mittee on muscle toxicity [7].
Adverse events leading to dose interruptions or reductions were reported in 32 % of patients in the 200 mg once daily group and 60 % of patients in the 800 mg once daily group [7]. Twenty two percent of sonidegib 200 mg once daily recipients and 36 % of sonidegib 800 mg once daily recip- ients, discontinued therapy as a result of adverse events. Serious adverse events were reported in 14 % of patients in the sonidegib 200 mg once daily group and in 30 % of patients in the sonidegib 800 mg once daily group [7].
Generally similar patterns of adverse events were observed in phase I/II trials in medulloblastoma [24] or other tumours potentially dependent on Hh signaling pathway such as myelofibrosis [25], chronic myeloid leu- kemia [27] and extensive stage small-cell lung cancer [26]. The US prescribing information contains a boxed warning regarding the risk of embryo-fetal death or severe birth defects when sonidegib is administered to a pregnant woman [4]. Females are advised to use effective contra- ception during treatment with sonidegib and for at least 20 months after the last dose, and males are advised to use condoms during treatment and for at least 8 months after the last dose. The prescribing information also contains warnings or precautions for musculoskeletal adverse reac- tions, which may be accompanied by elevated creatine phosphokinase [4].
2.5 Companion Diagnostic
Genoptix, a subsidiary of Novartis, is developing a com- panion diagnostic for sonidegib, to identify medulloblas- toma patients with the 5-gene signature that indicates Hh pathway activation. The five-gene Hh signature include GLI1, sphingosine kinase 1 (SPHK1), shroom family member 2 (SHROOM2), PDZ and LIM domain 3 (PDLIM3) and orthodenticle homeobox 2 (OTX2) [28]. The diagnostic agent will be used as a patient pre-selection tool. Clinical development is underway.
2.6 Ongoing Clinical Trials
2.6.1 Basal Cell carcinoma
The phase II BOLT trial, which is evaluating the efficacy of sonidegib in patients with locally advanced or metastatic BCC, is ongoing (NCT01327053); the primary analysis has been completed (Sect. 2.3.1) [7]. Additionally, Stanford University, in collaboration with National Cancer Institute, has initiated a study (presumably phase II) to assess the effi- cacy and safety of sonidegib in combination with buparlisib in patients with locally advanced or metastatic BCC (NCT02303041) and a phase II trial will investigate the effect of oral sonidegib in patients with BCC and prior exposure to Hh pathway inhibitors (EudraCT2012-004113-13).
2.6.2 Other Malignancies
With regard to other indications, phase II trials in haema- tological malignancies are planning to assess the safety and efficacy of sonidegib in combination with bortezomib in patients with relapsed/refractory multiple myeloma (NCT02254551). In addition, a phase II trial (NCT02086552) will evaluate the efficacy of sonidegib in combination with lenalidomide as maintenance therapy following autologous stem cell transplantation, in patients with refractory multiple myeloma and another phase II study (NCT01826214; EudraCT2012-004022-21) is being conducted to evaluate sonidegib in adult patients with relapsed/refractory acute leukaemia, and in elderly patients with previously untreated acute leukaemia.
Novartis is planning an uncontrolled phase II trial, to investigate efficacy and safety of once-daily sonidegib in patients with metastatic osteosarcoma (cohort 1), meta- static or unresectable chondrosarcoma (cohort 2), or Ewing’s sarcoma, desmoplastic small round cell tumour or rhabdomyosarcoma (cohort 3) in Australia and New Zealand (ACTRN12612000533897), and is conducting a multinational phase II trial to compare the efficacy and tolerability of sonidegib in patients with Hh pathway activated relapsed medulloblastoma (NCT01708174).
There are also ongoing phase I/II trials assessing soni- degib, alone or in combination with other chemothera- peutic drugs, in other indications, including myelofibrosis (NCT01787552; see Sect. 2.3.3), platinum resistant ovarian cancer (NCT02195973), myeloid malignancies
(NCT02129101) and borderline resectable pancreatic ade- nocarcinoma (NCT01431794). Additionally, several phase I trials are investigating sonidegib in patients with steroid- refractory chronic graft versus host disease following allogeneic haematopoietic stem cell transplantation (NCT02086513), advanced oesophageal or gastro-oe- sophageal junction cancer (NCT02138929), myelodys- plastic syndrome (NCT02323139), prostate cancer (NCT02111187), triple-negative advanced breast cancer (NCT02027376) [29], hepatocellular carcinoma (NCT02151864), castrate resistant prostate cancer (NCT02182622), pancreatic cancer (NCT02358161) and extensive stage small-cell lung cancer (NCT01579929; see Sect. 2.3.4).
3 Current Status
Sonidegib received its first global approval on 30 June 2015 in Switzerland and was approved on 24 July 2015 in the US for the treatment of adult patients with locally advanced BCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy [5, 6]. Furthermore, sonidegib was approved on 20 August 2015 in the EU for the treat- ment of adult patients with locally advanced BCC who are not amenable to curative surgery or radiation therapy [8].
Disclosure The preparation of this review was not supported by any external funding. During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. C. B. Burness is a salaried employee of Adis, Springer SBM.
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