Nintedanib: from discovery to the clinic.

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Drug Annotation

Nintedanib: From Discovery to the Clinic Gerald J Roth, Rudolf Binder, Florian Colbatzky, Claudia Dallinger, Rozsa Schlenker-Herceg, Frank Hilberg, Stefan-Lutz Wollin, and Rolf Kaiser J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm501562a • Publication Date (Web): 04 Dec 2014 Downloaded from http://pubs.acs.org on December 7, 2014

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Journal of Medicinal Chemistry

Nintedanib: From Discovery to the Clinic Gerald J. Roth,†* Rudolf Binder,§ Florian Colbatzky,‡ Claudia Dallinger,ǁ Rozsa SchlenkerHerceg,∞ Frank Hilberg,∇ Stefan-Lutz Wollin,┴ and Rolf Kaiser# †

Department of Medicinal Chemistry; ‡Department of Non-Clinical Drug Safety; §Department of

Drug Metabolism and Pharmacokinetics; ǁDepartment of Translational Medicine and Clinical Pharmacology; ┴Department of Respiratory Diseases Research; and #Corporate Division Medicine, TA Oncology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; ∞

Clinical Development and Medical Affairs, Respiratory, Boehringer Ingelheim Inc., Ridgefield,

CT, USA; ∇Boehringer Ingelheim RCV GmbH &Co.KG, A-1121 Vienna, Austria.

ACS Paragon Plus Environment


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ABSTRACT Nintedanib (BIBF1120) is a potent, oral, small-molecule tyrosine kinase inhibitor, also known as a triple angiokinase inhibitor, inhibiting three major signaling pathways involved in angiogenesis. Nintedanib targets proangiogenic and pro-fibrotic pathways mediated by the VEGFR family, the fibroblast growth factor receptor (FGFR) family, the platelet-derived growth factor receptor (PDGFR) family, as well as Src and Flt-3 kinases. The compound was identified during a lead optimization program for small-molecule inhibitors of angiogenesis and has since undergone extensive clinical investigation for the treatment of various solid tumors, and in patients with the debilitating lung disease idiopathic pulmonary fibrosis (IPF). Recent clinical evidence from phase III studies has shown that nintedanib has significant efficacy in the treatment of NSCLC, ovarian cancer and IPF. This review article provides a comprehensive summary of the preclinical and clinical research and development of nintedanib from the initial drug discovery process to the latest available clinical trial data.


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INTRODUCTION

In 1998, a lead optimization program to develop angiogenesis inhibitors for the treatment of cancer was initiated at Boehringer Ingelheim. The key characteristics of the initial target profile were selective inhibition of vascular endothelial growth factor receptor (VEGFR)-2 over other kinases, potent inhibition of endothelial cell proliferation, good oral bioavailability, and proven in vivo activity in tumor xenografts; and these characteristics guided the early optimization process. Nintedanib ethanesulfonate, a 6-methoxycarbonyl-substituted indolinone derivative (Figure 1), was identified during that program and has subsequently progressed to phase III clinical trial investigation.

O MeN

NH O

MeO O

N H

NMe

N

EtSO3H

1 BIBF1120 ethanesulfonate

Figure 1. Molecular structure of nintedanib ethanesulfonate.

STRUCTURE AND SYNTHESIS

The convergent syntheses of nintedanib (2) and its ethanesulfonate salt (1) have been described previously1-3 and comprise a sequence of five linear steps (including the formation of the final salt form) and a two-step sequence for the preparation of the aniline side chain (9). The reaction scheme shown in Figure 2 depicts an optimized synthesis route that can be used for the preparation of >100 g batches of the compounds.


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After a classical malonic ester addition to arene 3, the resulting nitro benzene (4) is hydrogenated under acidic conditions, furnishing the 6-methoxycarbonyl-substituted oxindole 5 via decarboxylative cyclization. Condensation of 5 with trimethyl orthobenzoate in acetic anhydride leads to compound 6, one of the two key building blocks of the synthesis. The concomitant N-acetylation of the oxindole activates the scaffold for the condensation reaction. The aniline side chain (9) can be prepared by a one-pot bromo-acetylation/amination of the para-nitro-phenylamine (7) using bromoacetyl bromide and N-methylpiperazine and a subsequent hydrogenation furnishing 9 as the second key building block. Condensation of both building blocks in an addition-elimination sequence and subsequent acetyl removal with piperidine furnishes 2 as free base (pKa = 7.9), which subsequently is converted into its monoethanesulfonate salt (1). Compound 1 is highly crystalline (mp = 305 °C), exhibits a log P of 3.0 and good aqueous solubility (>20 mg/mL in water).


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MEDICINAL CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIPS (SAR)

Hit finding for VEGFR-2 inhibition was initially based on a high throughput screening strategy. In parallel, selectivity testing of derivatives from a related kinase project (CDK4) revealed compound 10 (see Table 1) as a weakly potent, but already cellular active VEGFR-2 inhibitor.1 In addition, 10 was completely devoid of CDK4 activity, and when tested on a small kinase selectivity panel it revealed a specificity pattern that was clearly superior to those of other hit structures.


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Cl MeO

NO 2 O 3 malonic acid dimethyl ester, KOtBu then 3 CH(COOMe) 2 NHMe

MeO

NO 2 O 2N

O 4

7 bromoacetyl bromide N-methylpiperazine Li 2CO 3 , EtOAc

H 2 , Pd/C, AcOH

O

MeO

Me N

N H

O

O

O 2N

5

N NMe

8 (MeO) 3 CPh, Ac 2O H 2 , Pd/C, MeOH MeO Me N

O

MeO

N O

O

a) heat b) piperidine

Me

O

H 2N

N NMe

9

6 O MeN

N

NMe

NH O

MeO O

N H

2 EtSO3 H, MeOH

BIBF1120 ethanesulfonate 1


6

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Figure 2. Synthesis of nintedanib ethanesulfonate.


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We reasoned that this promising selectivity profile could potentially be attributed to the substituent in the 6-position of the oxindole core. Our hypothesis that substituents in this position should occupy the specificity pocket of the ATP binding region (see Figure 3) would later be confirmed by an X-ray structure of nintedanib and the kinase domain of VEGFR-2.4 Based on these findings, 10 was selected as the lead structure of the initial project. First synthesis campaigns were aimed at the generation of SAR and, in particular, improving the biochemical potency of 10.1 The overall SAR of the oxindole class are depicted in Figure 3. Replacing the central aryl moiety in the ribose pocket with smaller alkyl substituents turned out to be detrimental to the chemical stability of the molecules, probably due to the fact that only the phenyl moiety can adopt a strain-free perpendicular conformation to the rest of the molecule. This perpendicular conformation disrupts the overall flat compound shape and is probably one of the factors contributing to the good aqueous solubility of nintedanib. It was, therefore, decided to leave this position and the kinase hinge-binding motif unchanged. As expected, SAR in the 6position of the oxindole core are steep, and substitution has a dramatic impact on the overall selectivity profile. Whereas the non-substituted oxindole 11 (see Table 1) displayed low potency and less favorable selectivity over related kinases such as CDK4, InsR and IGF1R (at 1 µM), the substituent in the 6-position of the oxindole turned out to be a good handle to dial in or out kinase activity. By far the most potent variation discovered was the 6-nitro substitution (12, Table 1) that we refrained from taking into the optimization process due to the mutagenic potential of the nitro group. Chloro-substituted compounds were followed up for some time, but were eventually terminated because of a less attractive selectivity profile. Although estersubstituted oxindoles such as 14 were identified as potent inhibitors, the obvious risk of metabolic degradation by esterases was a concern. Only when 14 and derivatives demonstrated


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acceptable oral exposure in rodents were they taken into the optimization process as new leads. Selectivity testing revealed that compounds such as 14 display excellent kinase-specificity profiles when tested against a screening set of 40 kinases.5 Selectivity testing also identified inhibition of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), which was considered to be beneficial to the overall antiangiogenic profile of the compound. 6-Carboxy oxindoles such as 15 show no or limited activity on the VEGFR-2, FGFR or PDGFR receptors. Optimization of aryl ring substitution at R2 pointing toward the outer rim of the kinase pocket was straightforward. Shallow SAR allowed for fine-tuning of properties such as cellular activity and solubility. For most of the compounds, the biochemical potencies translated well into the inhibition of proliferation of human umbilical vein endothelial cells (HUVEC). Final optimization of R2 furnished a set of highly potent, selective, and orally available compounds such as BIBF1000 (16). After evaluation in xenograft experiments (Target Engagement section), chemistry manufacturing control (CMC) characterization, general pharmacology, and tolerability testing (Toxicology section), lead optimization concluded in 2001 with the promotion of nintedanib (2) into preclinical development.


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Figure 3. Structure-activity relationships of 6-substituted oxindoles.


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Table 1. Biological Activity of Key Compounds 2

R

N H O 1

R

N H

compd

R1

R2

IC50 (nM) VEGFR-2a

FGFR-1c

EC50 (nM) PDGFR-αc

HUVEC/ VEGFa

10

CONH2

4-CH2(piperidin-1-yl)

763 ± 198

NTd

NTd

342 ± 176

11

H


2112 ±

NTd

NTd

NTd

1215b 12

NO2


7±9

NTd

NTd

60 ± 10

13

Cl


129 ± 78b

NTd

NTd

49 ± 54

14

COOMe


36 ± 36b

NTd

NTd

103 ± 11b

15

COOH


>1000

NTd

NTd

NTd

16

COOMe

4-(NMe)-

61 ± 17

50 ± 4

20 ± 2

22 ± 11

COCH2NMe2


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

2e

COOMe

4-(NMe)COCH2-(4-

21 ± 13

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69 ± 70

59 ± 71

10 ± 13

methylpiperazin-1-yl) a

Values are averages ± standard deviation of at least three independent determinations. bFour independent

determinations. cSelectivity values are averages ± standard deviation of three independent determinations. dNot tested. .eNintedanib.

TARGET ENGAGEMENT

The preclinical development of nintedanib utilized in vitro inhibition assays to demonstrate that nintedanib inhibits a distinctive, narrow range of kinases at pharmacologically relevant concentrations (Table 2).4 Targeted kinases included all three VEGFR subtypes, FGFR types 1, 2, and 3, and PDGFR-α and -β. The ability of nintedanib to simultaneously target these three, distinct proangiogenic receptor classes may enhance its antitumor effects and overcome pathways of resistance to VEGF- and VEGFR-2-targeted agents. Nintedanib also inhibited Flt-3 and members of the Src-family (Src, Lyn, and Lck), which may have therapeutic potential for conditions such as hematologic diseases. Table 2. Summary of Nintedanib’s In Vitro Kinase Inhibition Profile4 Kinase

IC50 (nM)a

VEGFR-1

34 ± 15

VEGFR-2

21 ± 13

VEGFR-2 (mouse)

13 ± 4


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VEGFR-3

13 ± 10

FGFR-1

69 ± 70

FGFR-2

37 ± 2

FGFR-3

108 ± 41

FGFR-4

610 ± 117

PDGFR-α

59 ± 71

PDGFR-β

65 ± 7

InsR

>4000

IGF1R

>1000

EGFR

>50000

HER2

>50000

CDK1

>10000

CDK2

>10000

CDK4

>10000

Flt-3

26

Lck

16 ± 16

Lyn

195 ± 12


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Src a

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156 ± 40

Assays performed with adenosine 5′-triphosphate (ATP) concentrations at the respective Michaelis constant (Km).

Human kinases were tested except when stated otherwise. Data represent mean ± standard error of at least three determinations; IC50 values "greater than" indicate that half-maximum inhibition was not achieved at the highest concentration tested.

In vitro inhibition of VEGFR-2 was found to be sustained for at least 32 hours in VEGFR-2transfected NIH3T3 cells exposed to nintedanib for only 1 hour, a remarkably sustained duration of target kinase inhibition.4 Subsequent inhibition of VEGF-stimulated cell proliferation was demonstrated for endothelial cells derived from umbilical veins (HUVEC) and skin microvessels (HSMEC) (EC50 8 L/kg; Table 3). Detailed tissue distribution studies by means of whole body autoradiography or tissue dissection confirmed an extensive tissue distribution except in the CNS.

Nintedanib showed concentration-independent plasma protein binding in the concentration range of 50 to 2000 ng/mL with albumin being the major binding protein. The fraction of nintedanib bound was 97.8% in human plasma, 97.2% in mouse plasma, and 98.5% in rat plasma.

Elimination of nintedanib was mainly governed by ester cleavage and subsequent metabolic pathways. Considered along with the metabolite patterns of plasma and excreta, the metabolism of nintedanib was shown to be subdivided into the following principal reactions: 1) ester cleavage of the methyl ester of the 6-substituted oxindole, 2) oxidative N-demethylation of the piperazine moiety and 3) a combination of ester cleavage and oxidative N-demethylation.

The main excretion pathway was as metabolites via bile. Renal excretion after oral administration was low with 2.1% of dosed drug-related radioactivity in mice and 1.2% of the dose in rats excreted in urine.


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Table 3. Species Comparison of Plasma-derived PK Parameters of the Parent Drug After Single Administration of Nintedanib

Species

rata

mouse

cynomolgusb

rhesusb

oral

oral

i.v.

oral

i.v.

oral

i.v.

Nintedanib dose (mg/kg)

50

50

2

40

5

40

5

Cmax [ng/mL]

547

105

124

175

1300

311

1090

t½ [h]

5.15

ND

3.95

ND

5.95

ND

7.09

AUC [(ng·h)/mL]

2720

375

181

2390

2260

4440

2830

Clearance [mL/min/kg]

NA

NA

202

NA

37.5

NA

30.2

MRT [h]

5.19

ND

3.25

ND

3.82

ND

5.70

V(ss) [L/kg]

NA

NA

41.2

NA

8.64

NA

10.4

Bioavailability [%]

ND

11.9

NA

13.2

NA

23.8

NA

Method of Administration

a

Several formulations and dosages were tested. Within the dose range of 30 to 300 mg/kg, AUC0–24h and Cmax

increased proportional with dose. bSingle dose PK after i.v.-dosing was integrated in an oral dose range finding study. Additional dose groups were used. Only representative PK data are listed here. Linear dose dependency and no sex effect was observed. AUC = area under the curve; Cmax= maximal concentration; MRT = mean residence time; NA = not applicable; ND = not determined; t½ = half-life; V(ss) = volume of distribution at steady state.


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DISEASE AND MECHANISM OF ACTION Oncology. The clinical success of bevacizumab has established the principle of

antiangiogenesis as a valid treatment strategy in oncology. Bevacizumab in combination with chemotherapy significantly improves overall survival (OS) versus chemotherapy alone as firstline treatment for several malignancies, including NSCLC10 and colorectal cancer (CRC).11 Bevacizumab-based regimens are also an established second-line treatment option in patients with relapsed/refractory CRC. Antiangiogenic tyrosine kinase inhibitors have also been integrated into standard of care clinical practice for patients with other cancers, such as sunitinib, sorafenib, pazopanib or axitinib in RCC, and sorafenib in hepatocellular carcinoma (HCC) and differentiated thyroid carcinoma. Despite these successes, the limitations of current antiangiogenic agents are increasingly recognized, with insufficient efficacy and the development of resistance limiting the long-term success of VEGF-targeted therapies.12 Toxicities, such as hypertension, bleeding, risk of gastrointestinal perforation, dermatological conditions and mucositis, may also limit treatment with VEGF- or VEGFR inhibitors.13 Activation of alternative, redundant proangiogenic pathways has been implicated in resistance to VEGF inhibition, including FGFs, PDGFs, placental growth factor (PlGF), and TNF-α. The mammalian FGF-pathway family comprises 23 growth factor proteins (FGF-1 to -23) and four receptors (FGFR-1 to -4).14 Overexpression of various FGF ligands has been reported for a range of different tumor types.14 FGF-2, in particular, is a potent stimulator of angiogenesis15 that is frequently overexpressed in tumors and correlated with poor outcomes in NSCLC.16 Mutation or amplification of FGFR genes have been found in various human cancers.17 Notably, FGFR activation in endothelial cell culture and animal models leads to angiogenesis.14 Signaling via PDGF ligands (PDGF-A to PDGF-D) and


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the two forms of PDGF receptor (PDGFR-α and PDGFR-β), which is involved in physiological vessel maturation and the recruitment of pericytes, is also implicated in angiogenesis and cancer progression. Mutations involving upregulation of PDGF and/or PDGFR have been described in human cancers, and overexpression of PDGFR has been associated with poor prognosis.18 Thus nintedanib as a potent inhibitor of three proangiogenic pathway receptor families (VEGFR, FGFR, and PDGFR) was considered promising as an antiangiogenic anticancer therapy. Idiopathic Pulmonary Fibrosis. The potential for tyrosine kinase inhibition in the treatment of patients with IPF was also recognized during clinical development of nintedanib. IPF is a chronic and progressive, fibrotic lung disease associated with a short median survival post diagnosis of 2–3 years due to a lack of effective therapies.19 IPF is characterized by uncontrolled fibroblast/myofibroblast proliferation and differentiation, and excessive collagen deposition within the lung interstitium and alveolar space,20 leading to symptoms of cough and dyspnea, and ultimately to respiratory failure. The pathogenic mechanisms that give rise to IPF are not fully understood, but a number of tyrosine kinase receptors inhibited by nintedanib have been implicated as mediators. FGFR-1 and FGFR-2 are expressed on a variety of cells in the lungs of patients with IPF.21 Furthermore, FGF-2 stimulates proliferation of lung fibroblasts from patients with IPF22 and inhibition of FGF signaling reduces pulmonary fibrosis and improves survival in mouse models of IPF.23 PDGF stimulates proliferation, migration, and survival of myofibroblasts thought to be responsible for collagen deposition in IPF. VEGF expression also correlates with sub-epithelial fibrosis in


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patients with asthma,24 and anti-VEGF therapy shows some functional benefit in mouse models of IPF.25

HUMAN ADME

The clinical PK profile of nintedanib has been extensively investigated as monotherapy in healthy volunteers,26 and in patients with cancer as monotherapy and in combination with other agents in a number of phase I27-34 and phase II clinical trials.35,36 These studies show that nintedanib is rapidly absorbed after oral administration, with a time to maximum plasma concentrations of 1–3 hours.26,28 The mean terminal t1/2 of nintedanib is approximately 13–19 hours.26,28 Maximum plasma concentration (Cmax) of nintedanib and overall drug exposure (area under the plasma concentration-time curve [AUC]) showed dose-proportional increases with no decrease in exposure observed over a minimum 6-month treatment period.28 Following multiple twice-daily administration of nintedanib, only slight accumulation of nintedanib exposure was observed with a mean accumulation ratio of 1.33 based on Cmax and 1.66 based on AUC0–12 37 hours.

Inter-patient variability of PK parameters for nintedanib was moderate to high.26,28,37 No

PK interaction has been observed in phase I combination studies between nintedanib and the chemotherapeutic agents/regimens docetaxel,33 pemetrexed,32 carboplatin/paclitaxel,31 and FOLFOX6.38 In a pharmacological study of healthy volunteers using [14C]-radiolabeled nintedanib, a high apparent volume of distribution during the terminal phase was observed, indicating a high tissue distribution of the drug, and a high apparent total body clearance.26 Most [14C]-radioactivity (56.3%) was excreted within 24–48 hours and mass balance considered complete 96 hours after administration, with a total of 92.4% of [14C]-radioactivity recovered in urine and feces.


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Cumulative recovery of excreted [14C]-radioactivity revealed that urinary excretion for nintedanib is minor (approximately 0.7% over 72 hours) and that the major route of elimination is through metabolism, with metabolites excreted via the biliary system into the feces (93.4% over 120 hours).26 Nintedanib metabolism in healthy humans occurs predominantly by cleavage of the methyl ester moiety to the carboxylate, which is then conjugated to glucuronic acid, yielding the 1-Oacylglucuronide. Thus metabolism of nintedanib is predominantly CYP450 enzyme-independent, which may facilitate its combination with cytotoxic chemotherapies, such as docetaxel, that utilize CYP450 enzymes.

TOXICOLOGY

The toxic potential of nintedanib has been fully explored in a toxicological program including single-dose toxicity studies in mice and rats, repeat-dose toxicity studies up to 26 weeks in rats, up to 13 weeks in cynomolgus monkeys and up to 52 weeks in rhesus monkeys. In vitro and in vivo genotoxicity assays have been performed as well as reproductive and developmental toxicity studies in rats and rabbits, carcinogenicity studies in mice and rats, safety pharmacology studies in rats, and local tolerance studies in rats and rabbits. Single-dose safety studies in rats and mice concluded that the acute toxicity of nintedanib in these two species was low. In repeat-dose toxicology studies, all species except the rat showed dose-limiting adverse gastrointestinal reactions such as diarrhea and vomiting, but usually without prominent histopathological changes. In all animal species used for repeat-dose studies, only mild reversible elevations of liver transaminases were observed.


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In terms of histopathology, nintedanib induced pharmacologically mediated changes that may be considered so-called class effects of VEGFR inhibitors. These included epiphyseal growth plate thickening in the femur/tibia and sternum, dentopathy of the continuously growing incisors of rats, and mild cellular depletion of the bone marrow accompanied by minimal changes of red blood cell parameters. The presence of periodic acid-Schiff stain-positive hyaline intracytoplasmic granules in podocytes and glomerular endothelium was also observed, which did not exacerbate over time and did not compromise renal function. Because of the inhibition of tyrosine kinases such as Lck, Lyn and other members of the Src family of kinases by nintedanib, immunological investigations (phenotyping of lymphoid subpopulations in blood, spleen, and thymus, as well as determination of spleen natural killer cell activity) were performed in rats, cynomolgus monkeys, and rhesus monkeys, but no consistent adverse effects on the immune system were observed. No pertinent adverse effects of nintedanib on the cardiovascular and broncho-pulmonary system were observed in any of the repeat-dose toxicology studies. Furthermore, there was no evidence of a carcinogenic potential of nintedanib in 2-year carcinogenicity bioassays in mice or rats. Reproductive toxicology studies in rats and rabbits showed no effects on male fertility, but as anticipated from its pharmacological activity, nintedanib was associated with increases in early fetal resorptions and teratogenic effects, most prominently variations and malformations of the major blood vessels and skeleton. A standard battery of in vitro and in vivo genotoxicity assays showed no mutagenic potential for nintedanib, and safety pharmacology studies indicated no adverse cardiovascular, respiratory, or neurological effects with nintedanib.


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CLINICAL DATA

Nintedanib is currently under investigation in several oncology indications as well as for the treatment of IPF, and is in the most advanced stages of clinical development for the treatment of NSCLC. Table 4 summarizes the key results from phase III clinical studies with nintedanib. Oncology. The initial evidence of nintedanib’s tolerability and encouraging efficacy in patients with advanced NSCLC was noted in two phase I dose-finding studies of combination regimens with paclitaxel and carboplatin as first-line therapy31 or with pemetrexed as second-line treatment.32 Both studies determined the maximum tolerated nintedanib dose to be 200 mg b.i.d. Second- or third-line nintedanib monotherapy (150 or 250 mg b.i.d.) was evaluated in patients with advanced NSCLC and was subsequently assessed in a randomized, double-blind phase II study, which again indicated that nintedanib has a manageable safety profile and promising efficacy.35 Larger-scale evaluation of nintedanib in NSCLC was subsequently carried out in two multinational, randomized, double-blind, placebo-controlled phase III studies of a similar design. The LUME-Lung 1 study compared a regimen of nintedanib (200 mg b.i.d.) or placebo on days 2–21, plus docetaxel (75 mg/m² on day 1) as second-line therapy for patients with advanced NSCLC (NCT00805194).39 A total of 655 patients were randomized to nintedanib plus docetaxel and 659 to placebo plus docetaxel, and treated until unacceptable adverse events (AEs) or disease progression. The LUME-Lung 1 study met its primary endpoint: addition of nintedanib to docetaxel led to a significant reduction in the risk of progression free survival (PFS) in the overall study population (median 3.4 months in the nintedanib arm vs 2.7 months in the placebo arm; hazard


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ratio [HR] = 0.79 [95% CI 0.68–0.92]; p=0.002), regardless of patients’ histology. The study also met the key secondary endpoint of OS, which was tested in a pre-specified stepwise order: first in patients with adenocarcinoma histology who progressed 1 year for second-line therapy in unselected adenocarcinoma NSCLC over the preceding 10 years of clinical development. Consistent with these findings, patients with adenocarcinoma histology who had progressed

Proceedings: cell therapies for Parkinson's disease from discovery to clinic.

Tackling Crizotinib Resistance: The Pathway from Drug Discovery to the Pediatric Clinic.

Metabolomics for Biomarker Discovery: Moving to the Clinic.

From clones to clinic.

The Novel PKCθ from Benchtop to Clinic.

Special Issue - From Biobanks to the Clinic.

Cytokines: from clone to clinic.

Alpidem from pharmacology to clinic.

Anthelmintics - from discovery to resistance.

Support from the clinic.

Neurotoxin-related research: from the laboratory to the clinic.

Nintedanib in non-small cell lung cancer: from preclinical to approval.

Colorectal cancer stem cells: from the crypt to the clinic.

Achilles Tendinopathy: From the Basic Science to the Clinic.

Pharmacogenomics: from cell to clinic (Part 1).

Epileptic syndromes: From clinic to genetic.

Alzheimer's disease: from molecule to clinic.

Plants antioxidants: From laboratory to clinic.

Veterinary interventional oncology: from concept to clinic.

From concept to clinic: Mathematically informed immunotherapy.

Molecular imaging: from bench to clinic.

Translation of anticancer efficacy from nonclinical models to the clinic.

From laboratory to clinic: the development of an immunological reagent.

MECP2 disorders: from the clinic to mice and back.