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New Chemical Entities Entering Phase III Trials in 2013
CHAPTER TWENTY-SIX
New Chemical Entities Entering Phase III Trials in 2013 Gregory T. Notte Gilead Sciences Inc., San Mateo, California, USA
Content References
434
Selection Criteria – The Phase III clinical trial must have been registered with ClinicalTrials. gov.a – The chemical structure must be available. References describing the medicinal chemistry discovery effort are included if available. – It must be the first time that this compound has reached Phase III for any indication as a single agent or in combination. – The compound must be synthetic in origin. The following classes of drugs are not included: biologics; inorganic or organometallic compounds; ssRNA; dendrimers; endogenous substances; radiopharmaceuticals; natural polypeptides; herbal extracts. – New formulations or single enantiomers of a previously approved drug are not included; novel prodrugs are included. – Compounds meeting the criteria are shown as the free base or free acid except those containing quaternary nitrogens. – This list was compiled using publically available information.b It is intended to give an overview of small molecule chemical matter entering Phase III and may not be all-inclusive.
a
b
The selection criteria this year included compounds whose Phase III trial began in 2012, but the trial was not registered with Clinicaltrials.gov or the structure was not disclosed until 2013. The following two websites were used extensively in compiling this information: http://www. clinicaltrials.gov/ http://www.ama-assn.org/ama/pub/physician-resources/medical-science/unitedstates-adopted-names-council.page.Any additional information could be obtained via a web-search or from the Sponsor’s website.
Annual Reports in Medicinal Chemistry, Volume 49 ISSN 0065-7743 http://dx.doi.org/10.1016/B978-0-12-800167-7.00026-2
#
2014 Elsevier Inc. All rights reserved.
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418
Gregory T. Notte
Facts and Figures – In 2013, there were 1390 Phase III trials registered at ClinicalTrials.gov that were classified as having a “drug intervention.” – Of the registered trials, 43 molecules (3.1%) met the selection criteria. – For the molecules contained hereinc: • Average molecular weight ¼ 540 (range ¼ 151.7–1893.0) • Average c Log D ¼ 1.98 (range ¼ 8.26–7.87) – The top five indications from all trials were: • Type 1 and 2 diabetes (70 trials) • Breast cancer (35 trials) • Hepatitis C (31 trials) • Chronic obstructive pulmonary disorder (28 trials) • Rheumatoid arthritis (28 trials)
Overview of results from last 3 years Phase III trials registered
NCEs (%)
Avg MW
Avg c Log D
2011
1537
42 (2.7%)
542
3.6d
2012
1426
39 (2.7%)
505
1.97
2013
1390
43 (3.1%)
540
1.98
NCEs
Approved
NDA under review
Discontinuede
2011
42
4 (10%)
7 (17%)
12 (28%)
2012
39
3 (8%)
6 (15%)
1 (3%)
2013
43
–
–
–
c
d
e
Calculated using ACD labs software. MIM-D3 and Velcalcetide were excluded from the c Log D averages due to the large negative values that were obtained. These values were reported as c Log P and calculated using Chemdraw. Starting in 2012, ACD Labs was used to calculate c Log D. The designation of “discontinued” was applied to molecules for which publically available information indicated they would not be approved in the indication which was referenced in the original NCE chapter. In some cases, additional clinical development may still be ongoing.
1. Aclerastide (DSC-127)1
Sponsor: Derma MW/c Log D: 913.03/1.81 CAS#: 227803-63-6 Start/End Date: Feb 2013–Jul 2015 Indication: Diabetic foot ulcers Route of Admin: Topical MOA: Angiotensin receptor agonist ClinicalTrials.gov Identifier NCT01830348
H N
H2N O H2 N HO
N
NH N H
NH
OH O
H N
N H
O
O
O
H N
N H H
O H3 C
OH
N O
O
CH3
CH3
2. ARN-509 (JNJ-56021927)2
Sponsor: Aragon MW/c Log D: 477.43/1.30 CAS#: 956104-40-8 Start/End Date: Sep 2013–Dec 2016 Indication: Castration-resistant prostate cancer Route of Admin: Oral, 240 mg, qd MOA: Androgen receptor antagonist ClinicalTrials.gov Identifier: NCT01946204
O H 3C
F
N
N
N
S
N H
N F
O
F F
3. ASP-2151 (M-5520)3
Sponsor: Maruho MW/c Log D: 482.55/2.10 CAS#: 841301-32-4 Start/End Date: Aug 2013–Dec 2014 Indication: Herpes simplex Route of Admin: Oral, 200 mg, qd MOA: Helicase-primase inhibitor ClinicalTrials.gov Identifier: NCT01959295
H N N O N
O H3C
O N CH3
S O O
Continued
4. Beclabuvir (BMS-791325)4
Sponsor: Bristol-Myers Squibb MW/c Log D: 659.84/1.99 CAS#: 958002-33-0 Start/End Date: Dec 2013–Aug 2014 Indication: Hepatitis C virus Route of Admin: Oral, 75 mg, bid MOA: NS5B polymerase inhibitor ClinicalTrials.gov Identifier: NCT01973049
N N
O H3C
O O O S N N H CH3
CH3
N O
CH3
5. Binimetinib (MEK-162)5
Sponsor: Novartis MW/c Log D: 441.23/5.42 CAS#: 606143-89-9 Start/End Date: Jul 2013–Dec 2014 Indication: Metastatic or unresectable cutaneous melanoma Route of Admin: Oral, 45 mg, bid MOA: MEK inhibitor ClinicalTrials.gov Identifier: NCT01763164
Br
F HO
O
F HN H N
N N CH3
O
6. Cadazolid (ACT-179811)6
Sponsor: Actelion MW/c Log D: 585.55/0.78 CAS#: 1025097-10-2 Start/End Date: Nov 2013–Nov 2015 Indication: Clostridium difficile-associated diarrhea Route of Admin: Oral, 250 mg, bid MOA: Quinolone antibiotic ClinicalTrials.gov Identifier: NCT01987895
O O HO
N OH O F
N
N OH
F O
O
7. Cebranopadol (GRT-6005)7
Sponsor: Gru¨nenthal MW/c Log D: 378.48/4.15 CAS#: 863513-91-1 Start/End Date: Nov 2013–Mar 2016 Indication: Cancer related pain Route of Admin: Oral, 0.2–1.0 mg, qd MOA: Opiate receptor-like 1 agonist ClinicalTrials.gov Identifier: NCT01964378
CH3 H3C N H N O F
8. Ceritinib (LDK-378)8
Sponsor: Novartis MW/c Log D: 558.14/2.24 CAS#: 1032900-25-6 Start/End Date: Jun 2013–Jul 2017 Indication: Non-small cell lung cancer Route of Admin: Oral, 750 mg, qd MOA: ALK inhibitor ClinicalTrials.gov Identifier: NCT01828112
CH3 Cl
H3C
S O O CH3
NH
N
N H
N H
N
O
CH3 CH3
9. Decernotinib (VX-509)9
Sponsor: Vertex MW/c Log D: 392.38/2.26 CAS#: 944842-54-0 Start/End Date: Apr 2013–Mar 2016 Indication: Rheumatoid arthritis Route of Admin: Oral MOA: JAK3 Inhibitor ClinicalTrials.gov Identifier: NCT01830985
H N
F F F
H3C H N O
CH3
N
N
N
N H
Continued
10. Delafloxacin (ABT-492)10
Sponsor: Melinta Therapeutics MW/c Log D: 440.76/1.10 CAS#: 352458-37-8 Start/End Date: Apr 2013–Jun 2014 Indication: Acute bacterial skin infections Route of Admin: iv MOA: DNA topoisomerase inhibitor ClinicalTrials.gov Identifier: NCT01811732 11. Duvelisib (IPI-145)
O
O F
OH N
N Cl
HO
F
N
H2N F
11
Sponsor: Infinity MW/c Log D: 416.86/4.60 CAS#: 1201438-56-3 Start/End Date: Nov 2013–Aug 2015 Indication: Chronic lymphocytic leukemia Route of Admin: Oral, bid MOA: PI3Kδ/γ inhibitor ClinicalTrials.gov Identifier: NCT02004522 12. Elobixibat (AZD-7806)
Cl
O N
CH3 N
HN
N
N
NH
12
Sponsor: Ferring MW/c Log D: 695.89/2.71 CAS#: 439087-18-0 Start/End Date: Apr 2013–Aug 2014 Indication: Chronic idiopathic constipation Route of Admin: Oral, 5–10 mg MOA: Ileal bile acid transporter inhibitor ClinicalTrials.gov Identifier: NCT01827592
H3C
H3C
N S
O
S
O
CH3
O O
H N
O N H
OH O
13. Emixustat (ACU-4429)13 OH
Sponsor: Acucela MW/c Log D: 263.38/0.88 CAS#: 1141777-14-1 Start/End Date: Feb 2013–Jul 2016 Indication: Dry age-related macular degeneration Route of Admin: Oral, 2.5–10 mg, qd MOA: Retinoid isomerohydrolase inhibitor ClinicalTrials.gov Identifier: NCT01802866
O
NH2
14. Encorafenib (LGX-818)14 CH3 Sponsor: Novartis MW/c Log D: 540.01/1.09 N H3C CAS#: 1269440-17-6 N Start/End Date: Sep 2013–Jun 2017 F Indication: Metastatic melanoma with BRAF V600 O O mutation Route of Admin: Oral, 300–450 mg, qd (alone or in H3C S N H combination with MEK-162) MOA: B-Raf inhibitor ClinicalTrials.gov Identifier: NCT01909453
H N
N N
CH3 O N H
O
CH3
Cl
15. Eravacycline (TP-434)15
Sponsor: Tetraphase MW/c Log D: 558.56/2.48 CAS#: 1207283-85-9 Start/End Date: Aug 2013–Jan 2015 Indication: Complicated intra-abdominal infection Route of Admin: iv MOA: Tetracycline antibiotic ClinicalTrials.gov Identifier: NCT01844856
F O N
N H
H
H3C CH3 N H OH NH2
OH
O HO OHO
O
Continued
16. Erismodegib (LDE-225)16
Sponsor: Novartis MW/c Log D: 485.5/5.42 CAS#: 956697-53-3 Start/End Date: May 2013–Aug 2016 Indication: Medulloblastoma Route of Admin: Oral MOA: Smoothened antagonist ClinicalTrials.gov Identifier: NCT01708174
F F
H N
F CH3 O
O
N
CH3
N O CH3
17. Ertugliflozin (PF-4971729)17
Sponsor: Merck Sharp & Dohme MW/c Log D: 436.88/6.49 CAS#: 1210344-57-2 Start/End Date: Oct 2013–Aug 2015 Indication: Type 2 diabetes mellitus Route of Admin: Oral, 5–15 mg, qd MOA: SGLT2 inhibitor ClinicalTrials.gov Identifier: NCT01958671
Cl O
HO
O OH
HO OH
18. Favipiravir (T-705)18
Sponsor: MediVector MW/c Log D: 157.1/1.72 CAS#: 259793-96-9 Start/End Date: Dec 2013–Dec 2014 Indication: Influenza Route of Admin: Oral, bid MOA: DNA directed RNA polymerase inhibitor ClinicalTrials.gov Identifier: NCT02008344
O F
N N
NH2 OH
O
CH3
19. Latanoprostene bunod (NCX-116)19
Sponsor: Bausch & Lomb MW/c Log D: 507.62/3.97 CAS#: 860005-21-6 Start/End Date: Jan 2013–Jun 2014 Indication: Open-angle glaucoma Route of Admin: ophthalmic solution, QD MOA: Nitric oxide donor ClinicalTrials.gov Identifier: NCT01749930
HO
O
O
NO2
O HO
OH
20. LEE-01120
Sponsor: Novartis MW/c Log D: 434.54/1.96 CAS#: 1211441-98-3 Start/End Date: Dec 2013–Jan 2017 Indication: Advanced breast cancer Route of Admin: Oral, 600 mg, qd MOA: CDK4/6 inhibitor ClinicalTrials.gov Identifier: NCT01958021
N N
H N
N N N
HN
O
CH3 N CH3
21. Lu AE5805421
Sponsor: Lundbeck MW/c Log D: 398.37/2.59 CAS#: 467459-31-0 Start/End Date: Oct 2013–Sep 2015 Indication: Alzheimer’s disease Route of Admin: Oral, 30–60 mg, qd MOA: 5 HT6R antagonist ClinicalTrials.gov Identifier: NCT01955161
F
H N HN
F F
O F F
Continued
22. Lumacaftor (VX-809)22
Sponsor: Vertex MW/c Log D: 452.41/2.29 CAS#: 936727-05-8 Start/End Date: Mar 2013–May 2014 Indication: Cystic fibrosis, homozygous for the F508del CFTR Mutation Route of Admin: Oral, 600 mg, qd/400 mg, bid MOA: ΔF508-CFTR corrector ClinicalTrials.gov Identifier: NCT01807923
F
O
F
O
H N
OH
N
O
CH3
O
23. MIM-D323
Sponsor: Mimetogen MW/c Log D: 580.54/8.26 CAS#: 263251-78-1 Start/End Date: Oct 2013–Jun 2014 Indication: Dry eye Route of Admin: Ophthalmic solution MOA: TrkA receptor agonist ClinicalTrials.gov Identifier: NCT01960010
O O2N
N H O O NH HO
24. Momelotinib (GS-0387)
OH
O
O NH2
HN N H
O
O
24
Sponsor: Gilead MW/c Log D: 414.46/1.21 CAS# 1056634-68-4 Start/End Date: Oct 2013–Jun 2016 Indication: Primary myelofibrosis Route of Admin: Oral, qd MOA: JAK1/2 inhibitor ClinicalTrials.gov Identifier: NCT01969838
O N
N H
H N
N N
N O
25. Naldemedine (S-297995)25
Sponsor: Shionogi MW/c Log D: 570.64/1.57 CAS#: 916072-89-4 Start/End Date: Aug 2013–Jul 2015 Indication: Opioid-induced constipation Route of Admin: Oral, qd MOA: Opioid receptor antagonist ClinicalTrials.gov Identifier: NCT01965158
N
N
OH O O
HO
OH
O
N
N H
CH3 CH3
O
NH2
26. Niraparib (MK-4827)26
Sponsor: Tesaro MW/c Log D: 320.39/0.49 CAS#: 1038915-60-4 Start/End Date: Jun 2013–Mar 2016 Indication: Platinum-sensitive ovarian cancer Route of Admin: Oral, qd MOA: PARP-1/2 inhibitor ClinicalTrials.gov Identifier: NCT01847274
N
HN N
27. Olaparib (AZD-2281)27
Sponsor: AstraZeneca MW/c Log D: 434.46/0.0 CAS#: 763113-22-0 Start/End Date: Aug 2013–Jul 2016 Indication: BRCA mutated ovarian cancer Route of Admin: Oral, 300 mg, bid MOA: PARP-1/2/3 inhibitor ClinicalTrials.gov Identifier: NCT01844986
O F
N N
O
N HN O Continued
28. Ombitasvir (ABT-267)28
Sponsor: AbbVie MW/c Log D: 894.11/6.29 CAS#: 1258226-87-7 Start/End Date: Nov 2012–Oct 2013 Indication: HCV infection Route of Admin: Oral, qd MOA: NS5A inhibitor ClinicalTrials.gov Identifier: NCT01716585
H3C CH3 H 3C
H3C
H3C O
CH3
N H
N
O
H N
H N N
O
O
29. Pacritinib (SB-1518)29 H N
Sponsor: Cell therapeutics MW/c Log D: 472.58/2.04 CAS#: 937272-79-2 Start/End Date: Dec 2012–Aug 2014 Indication: Primary myelofibrosis Route of Admin: Oral, 400 mg, qd MOA: Jak2 inhibitor ClinicalTrials.gov Identifier: NCT01773187
N
N N
O O O
30. Palbociclib (PD-332991)30
Sponsor: Pfizer MW/c Log D: 447.53/0.10 CAS#: 571190-30-2 Start/End Date: Feb 2013–Mar 2015 Indication: Breast cancer Route of Admin: Oral, 125 mg, qd MOA: CDK 4/6 inhibitor ClinicalTrials.gov Identifier: NCT01740427
CH3 O
HN N
CH3
N N
N H
N
N
O
O
H3 C
CH3 O
N
N H
O
O
CH3
31. Pefcalcitol (M-518101)31 O
Sponsor: Maruho MW/c Log D: 519.54/5.42 CAS#: 381212-03-9 Start/End Date: Oct 2013–Sep 2014 Indication: Plaque psoriasis Route of Admin: Topical MOA: Vitamin D analog ClinicalTrials.gov Identifier: NCT01989429
H3C H3C
F F N H F
F F
H
HO
32. Polmacoxib (CG100649)
O
OH
32
Sponsor: Crystal Genomics MW/c Log D: 361.39/2.35 CAS#: 301692-76-2 Start/End Date: Mar 2013–Dec 2013 Indication: Osteoarthritis Route of Admin: Oral, 2 mg MOA: Cyclooxygenase 2 inhibitor ClinicalTrials.gov Identifier: NCT01765296
O H3C
O S NH 2
O
H3C
F O
33. Reparixin (DF-1681)33
Sponsor: Dompe´ MW/c Log D: 283.39/0.47 CAS#: 266359-83-5 Start/End Date: Jul 2012–May 2014 Indication: Islet transplantation in diabetes mellitus type 1 Route of Admin: iv MOA: CXCR1/CXCR2/IL-8 antagonist ClinicalTrials.gov Identifier: NCT01817959
O
O S N H 3C H
CH3
O
CH3 CH3
Continued
34. Retagliptin (SP-2086)34
Sponsor: Jiangsu HengRui Medicine MW/c Log D: 464.36/1.73 CAS#: 1174122-54-3 Start/End Date: Apr 2013–Jan 2014 Indication: Type 2 diabetes mellitus Route of Admin: Oral, 50 mg, qd or bid MOA: Dipeptidyl peptidase IV inhibitor ClinicalTrials.gov Identifier: NCT01970046
F
F F
H3C
F
N
N
N
O
O
O
NH2
35. Selumetinib (ARRY-886)35
Sponsor: AstraZeneca MW/c Log D: 457.68/5.55 CAS#: 606143-52-6 Start/End Date: Sep 2013–Jul 2016 Indication: Non-small cell lung cancer with KRAS mutation Route of Admin: Oral, 75 mg, bid MOA: MEK inhibitor ClinicalTrials.gov Identifier: NCT01933932
Br
Cl
HO
O
F HN H N
N N CH3
O
36. Talazoparib (BMN-673)36
Sponsor: BioMarin MW/c Log D: 380.35/1.91 CAS#: 1207456-01-6 Start/End Date: Oct 2013–Jun 2016 Indication: BRCA mutated breast cancer Route of Admin: Oral, 1.0 mg, qd MOA: PARP-1/2 inhibitor ClinicalTrials.gov Identifier: NCT01945775
F F
F
N N
NH
N
H 3C N HN
F O
37. Tenofovir alafenamide (GS-7340)37
Sponsor: Gilead MW/c Log D: 476.47/2.20 CAS#: 379270-37-8 Start/End Date: Dec 2012–Sep 2014 Indication: HIV infection Route of Admin: Oral, 10 mg, qd MOA: Reverse transcriptase inhibitor ClinicalTrials.gov Identifier: NCT01780506
NH2 N N
H3C
N N O
O P O NH CH3
O
H3C
CH3
O
38. Tetrabenazine-d6 (SD-809)38 O
Sponsor: Auspex MW/c Log D: 323.46/3.43 CAS#: 1221885-59-1 O D Start/End Date: Jun 2013–Aug 2014 D Indication: Chorea D O Route of Admin: Oral, 6–12 mg D MOA: Vesicular monoamine transporter 2 inhibitor D D ClinicalTrials.gov Identifier: NCT01795859
CH3 CH3
N
39. Velcalcetide (AMG-416)39
Sponsor: Amgen MW/c Log D: 1016.19/ CAS#: 1262780-97-1 Start/End Date: Jul 2013–May 2015 Indication: Secondary hyperparathyroidism Route of Admin: iv MOA: Calcium-sensing receptor agonist ClinicalTrials.gov Identifier: NCT01785875
O H2N
H N
H2N
NH
O
H2N O
N H
H N
H2N
NH
O
H N
N H CH3 O NH H2N
H N
H2N
NH
O
H N O
N H
OH S H N
CH3 O
O N H
CH3
N H Continued
40. Venetoclax (ABT-199)40
Sponsor: AbbVie MW/c Log D: 868.44/7.87 CAS#: 1257044-40-8 Start/End Date: Dec 2013–Aug 2018 Indication: Chronic lymphocytic leukemia Route of Admin: Oral, 400 mg, qd MOA: Bcl-2 inhibitor ClinicalTrials.gov Identifier: NCT02005471
H3C
CH3
NH N
O
Cl
N N
O
HN O2N
O
S
H N O O
41. Veruprevir (ABT-450)41
Sponsor: AbbVie MW/c Log D: 765.88/0.87 CAS#: 1216941-48-8 Start/End Date: Aug 2012–Jan 2014 Indication: HCV infection Route of Admin: Oral, qd, with ritonavir MOA: NS3 protease inhibitor ClinicalTrials.gov Identifier: NCT01674725
N H 3C
O
N H N
N O
H N
N O
O
O O O S N H
42. Volasertib (BI-6727)42
Sponsor: Boehringer Ingelheim MW/c Log D: 618.81/1.72 CAS#: 755038-65-4 Start/End Date: Jan 2013–Jan 2016 Indication: Acute myeloid leukemia Route of Admin: iv MOA: Polo-like kinase-1 inhibitor ClinicalTrials.gov Identifier: NCT01721876
N O H3C
CH3
CH3
N
O
N
N N
N
O N H
N H
CH3
H3C
43. Zoptarelin Doxorubicin (AN-152)43
Sponsor: AEterna Zentaris MW/c Log D: 1893.01/2.44 CAS#: 139570-93-7 Start/End Date: Apr 2013–Dec 2015 Indication: Endometrial cancer Route of Admin: iv MOA: DNA topoisomerase II inhibitor ClinicalTrials.gov Identifier: NCT01767155
Glp-His-Trp-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH2 O
O
OH
O OH
H3C
O
O H3C
OH O
HO NH2
O
NH O
O
434
Gregory T. Notte
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New Chemical Entities Entering Phase III Trials in 2013
18. 19. 20. 21.
22. 23. 24.
25. 26.
27.
28. 29.
30. 31.
32. 33.
435
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New Chemical Entities Entering Phase III Trials in 2013 Gregory T. Notte Gilead Sciences Inc., San Mateo, California, USA
Content References
434
Selection Criteria – The Phase III clinical trial must have been registered with ClinicalTrials. gov.a – The chemical structure must be available. References describing the medicinal chemistry discovery effort are included if available. – It must be the first time that this compound has reached Phase III for any indication as a single agent or in combination. – The compound must be synthetic in origin. The following classes of drugs are not included: biologics; inorganic or organometallic compounds; ssRNA; dendrimers; endogenous substances; radiopharmaceuticals; natural polypeptides; herbal extracts. – New formulations or single enantiomers of a previously approved drug are not included; novel prodrugs are included. – Compounds meeting the criteria are shown as the free base or free acid except those containing quaternary nitrogens. – This list was compiled using publically available information.b It is intended to give an overview of small molecule chemical matter entering Phase III and may not be all-inclusive.
a
b
The selection criteria this year included compounds whose Phase III trial began in 2012, but the trial was not registered with Clinicaltrials.gov or the structure was not disclosed until 2013. The following two websites were used extensively in compiling this information: http://www. clinicaltrials.gov/ http://www.ama-assn.org/ama/pub/physician-resources/medical-science/unitedstates-adopted-names-council.page.Any additional information could be obtained via a web-search or from the Sponsor’s website.
Annual Reports in Medicinal Chemistry, Volume 49 ISSN 0065-7743 http://dx.doi.org/10.1016/B978-0-12-800167-7.00026-2
#
2014 Elsevier Inc. All rights reserved.
417
418
Gregory T. Notte
Facts and Figures – In 2013, there were 1390 Phase III trials registered at ClinicalTrials.gov that were classified as having a “drug intervention.” – Of the registered trials, 43 molecules (3.1%) met the selection criteria. – For the molecules contained hereinc: • Average molecular weight ¼ 540 (range ¼ 151.7–1893.0) • Average c Log D ¼ 1.98 (range ¼ 8.26–7.87) – The top five indications from all trials were: • Type 1 and 2 diabetes (70 trials) • Breast cancer (35 trials) • Hepatitis C (31 trials) • Chronic obstructive pulmonary disorder (28 trials) • Rheumatoid arthritis (28 trials)
Overview of results from last 3 years Phase III trials registered
NCEs (%)
Avg MW
Avg c Log D
2011
1537
42 (2.7%)
542
3.6d
2012
1426
39 (2.7%)
505
1.97
2013
1390
43 (3.1%)
540
1.98
NCEs
Approved
NDA under review
Discontinuede
2011
42
4 (10%)
7 (17%)
12 (28%)
2012
39
3 (8%)
6 (15%)
1 (3%)
2013
43
–
–
–
c
d
e
Calculated using ACD labs software. MIM-D3 and Velcalcetide were excluded from the c Log D averages due to the large negative values that were obtained. These values were reported as c Log P and calculated using Chemdraw. Starting in 2012, ACD Labs was used to calculate c Log D. The designation of “discontinued” was applied to molecules for which publically available information indicated they would not be approved in the indication which was referenced in the original NCE chapter. In some cases, additional clinical development may still be ongoing.
1. Aclerastide (DSC-127)1
Sponsor: Derma MW/c Log D: 913.03/1.81 CAS#: 227803-63-6 Start/End Date: Feb 2013–Jul 2015 Indication: Diabetic foot ulcers Route of Admin: Topical MOA: Angiotensin receptor agonist ClinicalTrials.gov Identifier NCT01830348
H N
H2N O H2 N HO
N
NH N H
NH
OH O
H N
N H
O
O
O
H N
N H H
O H3 C
OH
N O
O
CH3
CH3
2. ARN-509 (JNJ-56021927)2
Sponsor: Aragon MW/c Log D: 477.43/1.30 CAS#: 956104-40-8 Start/End Date: Sep 2013–Dec 2016 Indication: Castration-resistant prostate cancer Route of Admin: Oral, 240 mg, qd MOA: Androgen receptor antagonist ClinicalTrials.gov Identifier: NCT01946204
O H 3C
F
N
N
N
S
N H
N F
O
F F
3. ASP-2151 (M-5520)3
Sponsor: Maruho MW/c Log D: 482.55/2.10 CAS#: 841301-32-4 Start/End Date: Aug 2013–Dec 2014 Indication: Herpes simplex Route of Admin: Oral, 200 mg, qd MOA: Helicase-primase inhibitor ClinicalTrials.gov Identifier: NCT01959295
H N N O N
O H3C
O N CH3
S O O
Continued
4. Beclabuvir (BMS-791325)4
Sponsor: Bristol-Myers Squibb MW/c Log D: 659.84/1.99 CAS#: 958002-33-0 Start/End Date: Dec 2013–Aug 2014 Indication: Hepatitis C virus Route of Admin: Oral, 75 mg, bid MOA: NS5B polymerase inhibitor ClinicalTrials.gov Identifier: NCT01973049
N N
O H3C
O O O S N N H CH3
CH3
N O
CH3
5. Binimetinib (MEK-162)5
Sponsor: Novartis MW/c Log D: 441.23/5.42 CAS#: 606143-89-9 Start/End Date: Jul 2013–Dec 2014 Indication: Metastatic or unresectable cutaneous melanoma Route of Admin: Oral, 45 mg, bid MOA: MEK inhibitor ClinicalTrials.gov Identifier: NCT01763164
Br
F HO
O
F HN H N
N N CH3
O
6. Cadazolid (ACT-179811)6
Sponsor: Actelion MW/c Log D: 585.55/0.78 CAS#: 1025097-10-2 Start/End Date: Nov 2013–Nov 2015 Indication: Clostridium difficile-associated diarrhea Route of Admin: Oral, 250 mg, bid MOA: Quinolone antibiotic ClinicalTrials.gov Identifier: NCT01987895
O O HO
N OH O F
N
N OH
F O
O
7. Cebranopadol (GRT-6005)7
Sponsor: Gru¨nenthal MW/c Log D: 378.48/4.15 CAS#: 863513-91-1 Start/End Date: Nov 2013–Mar 2016 Indication: Cancer related pain Route of Admin: Oral, 0.2–1.0 mg, qd MOA: Opiate receptor-like 1 agonist ClinicalTrials.gov Identifier: NCT01964378
CH3 H3C N H N O F
8. Ceritinib (LDK-378)8
Sponsor: Novartis MW/c Log D: 558.14/2.24 CAS#: 1032900-25-6 Start/End Date: Jun 2013–Jul 2017 Indication: Non-small cell lung cancer Route of Admin: Oral, 750 mg, qd MOA: ALK inhibitor ClinicalTrials.gov Identifier: NCT01828112
CH3 Cl
H3C
S O O CH3
NH
N
N H
N H
N
O
CH3 CH3
9. Decernotinib (VX-509)9
Sponsor: Vertex MW/c Log D: 392.38/2.26 CAS#: 944842-54-0 Start/End Date: Apr 2013–Mar 2016 Indication: Rheumatoid arthritis Route of Admin: Oral MOA: JAK3 Inhibitor ClinicalTrials.gov Identifier: NCT01830985
H N
F F F
H3C H N O
CH3
N
N
N
N H
Continued
10. Delafloxacin (ABT-492)10
Sponsor: Melinta Therapeutics MW/c Log D: 440.76/1.10 CAS#: 352458-37-8 Start/End Date: Apr 2013–Jun 2014 Indication: Acute bacterial skin infections Route of Admin: iv MOA: DNA topoisomerase inhibitor ClinicalTrials.gov Identifier: NCT01811732 11. Duvelisib (IPI-145)
O
O F
OH N
N Cl
HO
F
N
H2N F
11
Sponsor: Infinity MW/c Log D: 416.86/4.60 CAS#: 1201438-56-3 Start/End Date: Nov 2013–Aug 2015 Indication: Chronic lymphocytic leukemia Route of Admin: Oral, bid MOA: PI3Kδ/γ inhibitor ClinicalTrials.gov Identifier: NCT02004522 12. Elobixibat (AZD-7806)
Cl
O N
CH3 N
HN
N
N
NH
12
Sponsor: Ferring MW/c Log D: 695.89/2.71 CAS#: 439087-18-0 Start/End Date: Apr 2013–Aug 2014 Indication: Chronic idiopathic constipation Route of Admin: Oral, 5–10 mg MOA: Ileal bile acid transporter inhibitor ClinicalTrials.gov Identifier: NCT01827592
H3C
H3C
N S
O
S
O
CH3
O O
H N
O N H
OH O
13. Emixustat (ACU-4429)13 OH
Sponsor: Acucela MW/c Log D: 263.38/0.88 CAS#: 1141777-14-1 Start/End Date: Feb 2013–Jul 2016 Indication: Dry age-related macular degeneration Route of Admin: Oral, 2.5–10 mg, qd MOA: Retinoid isomerohydrolase inhibitor ClinicalTrials.gov Identifier: NCT01802866
O
NH2
14. Encorafenib (LGX-818)14 CH3 Sponsor: Novartis MW/c Log D: 540.01/1.09 N H3C CAS#: 1269440-17-6 N Start/End Date: Sep 2013–Jun 2017 F Indication: Metastatic melanoma with BRAF V600 O O mutation Route of Admin: Oral, 300–450 mg, qd (alone or in H3C S N H combination with MEK-162) MOA: B-Raf inhibitor ClinicalTrials.gov Identifier: NCT01909453
H N
N N
CH3 O N H
O
CH3
Cl
15. Eravacycline (TP-434)15
Sponsor: Tetraphase MW/c Log D: 558.56/2.48 CAS#: 1207283-85-9 Start/End Date: Aug 2013–Jan 2015 Indication: Complicated intra-abdominal infection Route of Admin: iv MOA: Tetracycline antibiotic ClinicalTrials.gov Identifier: NCT01844856
F O N
N H
H
H3C CH3 N H OH NH2
OH
O HO OHO
O
Continued
16. Erismodegib (LDE-225)16
Sponsor: Novartis MW/c Log D: 485.5/5.42 CAS#: 956697-53-3 Start/End Date: May 2013–Aug 2016 Indication: Medulloblastoma Route of Admin: Oral MOA: Smoothened antagonist ClinicalTrials.gov Identifier: NCT01708174
F F
H N
F CH3 O
O
N
CH3
N O CH3
17. Ertugliflozin (PF-4971729)17
Sponsor: Merck Sharp & Dohme MW/c Log D: 436.88/6.49 CAS#: 1210344-57-2 Start/End Date: Oct 2013–Aug 2015 Indication: Type 2 diabetes mellitus Route of Admin: Oral, 5–15 mg, qd MOA: SGLT2 inhibitor ClinicalTrials.gov Identifier: NCT01958671
Cl O
HO
O OH
HO OH
18. Favipiravir (T-705)18
Sponsor: MediVector MW/c Log D: 157.1/1.72 CAS#: 259793-96-9 Start/End Date: Dec 2013–Dec 2014 Indication: Influenza Route of Admin: Oral, bid MOA: DNA directed RNA polymerase inhibitor ClinicalTrials.gov Identifier: NCT02008344
O F
N N
NH2 OH
O
CH3
19. Latanoprostene bunod (NCX-116)19
Sponsor: Bausch & Lomb MW/c Log D: 507.62/3.97 CAS#: 860005-21-6 Start/End Date: Jan 2013–Jun 2014 Indication: Open-angle glaucoma Route of Admin: ophthalmic solution, QD MOA: Nitric oxide donor ClinicalTrials.gov Identifier: NCT01749930
HO
O
O
NO2
O HO
OH
20. LEE-01120
Sponsor: Novartis MW/c Log D: 434.54/1.96 CAS#: 1211441-98-3 Start/End Date: Dec 2013–Jan 2017 Indication: Advanced breast cancer Route of Admin: Oral, 600 mg, qd MOA: CDK4/6 inhibitor ClinicalTrials.gov Identifier: NCT01958021
N N
H N
N N N
HN
O
CH3 N CH3
21. Lu AE5805421
Sponsor: Lundbeck MW/c Log D: 398.37/2.59 CAS#: 467459-31-0 Start/End Date: Oct 2013–Sep 2015 Indication: Alzheimer’s disease Route of Admin: Oral, 30–60 mg, qd MOA: 5 HT6R antagonist ClinicalTrials.gov Identifier: NCT01955161
F
H N HN
F F
O F F
Continued
22. Lumacaftor (VX-809)22
Sponsor: Vertex MW/c Log D: 452.41/2.29 CAS#: 936727-05-8 Start/End Date: Mar 2013–May 2014 Indication: Cystic fibrosis, homozygous for the F508del CFTR Mutation Route of Admin: Oral, 600 mg, qd/400 mg, bid MOA: ΔF508-CFTR corrector ClinicalTrials.gov Identifier: NCT01807923
F
O
F
O
H N
OH
N
O
CH3
O
23. MIM-D323
Sponsor: Mimetogen MW/c Log D: 580.54/8.26 CAS#: 263251-78-1 Start/End Date: Oct 2013–Jun 2014 Indication: Dry eye Route of Admin: Ophthalmic solution MOA: TrkA receptor agonist ClinicalTrials.gov Identifier: NCT01960010
O O2N
N H O O NH HO
24. Momelotinib (GS-0387)
OH
O
O NH2
HN N H
O
O
24
Sponsor: Gilead MW/c Log D: 414.46/1.21 CAS# 1056634-68-4 Start/End Date: Oct 2013–Jun 2016 Indication: Primary myelofibrosis Route of Admin: Oral, qd MOA: JAK1/2 inhibitor ClinicalTrials.gov Identifier: NCT01969838
O N
N H
H N
N N
N O
25. Naldemedine (S-297995)25
Sponsor: Shionogi MW/c Log D: 570.64/1.57 CAS#: 916072-89-4 Start/End Date: Aug 2013–Jul 2015 Indication: Opioid-induced constipation Route of Admin: Oral, qd MOA: Opioid receptor antagonist ClinicalTrials.gov Identifier: NCT01965158
N
N
OH O O
HO
OH
O
N
N H
CH3 CH3
O
NH2
26. Niraparib (MK-4827)26
Sponsor: Tesaro MW/c Log D: 320.39/0.49 CAS#: 1038915-60-4 Start/End Date: Jun 2013–Mar 2016 Indication: Platinum-sensitive ovarian cancer Route of Admin: Oral, qd MOA: PARP-1/2 inhibitor ClinicalTrials.gov Identifier: NCT01847274
N
HN N
27. Olaparib (AZD-2281)27
Sponsor: AstraZeneca MW/c Log D: 434.46/0.0 CAS#: 763113-22-0 Start/End Date: Aug 2013–Jul 2016 Indication: BRCA mutated ovarian cancer Route of Admin: Oral, 300 mg, bid MOA: PARP-1/2/3 inhibitor ClinicalTrials.gov Identifier: NCT01844986
O F
N N
O
N HN O Continued
28. Ombitasvir (ABT-267)28
Sponsor: AbbVie MW/c Log D: 894.11/6.29 CAS#: 1258226-87-7 Start/End Date: Nov 2012–Oct 2013 Indication: HCV infection Route of Admin: Oral, qd MOA: NS5A inhibitor ClinicalTrials.gov Identifier: NCT01716585
H3C CH3 H 3C
H3C
H3C O
CH3
N H
N
O
H N
H N N
O
O
29. Pacritinib (SB-1518)29 H N
Sponsor: Cell therapeutics MW/c Log D: 472.58/2.04 CAS#: 937272-79-2 Start/End Date: Dec 2012–Aug 2014 Indication: Primary myelofibrosis Route of Admin: Oral, 400 mg, qd MOA: Jak2 inhibitor ClinicalTrials.gov Identifier: NCT01773187
N
N N
O O O
30. Palbociclib (PD-332991)30
Sponsor: Pfizer MW/c Log D: 447.53/0.10 CAS#: 571190-30-2 Start/End Date: Feb 2013–Mar 2015 Indication: Breast cancer Route of Admin: Oral, 125 mg, qd MOA: CDK 4/6 inhibitor ClinicalTrials.gov Identifier: NCT01740427
CH3 O
HN N
CH3
N N
N H
N
N
O
O
H3 C
CH3 O
N
N H
O
O
CH3
31. Pefcalcitol (M-518101)31 O
Sponsor: Maruho MW/c Log D: 519.54/5.42 CAS#: 381212-03-9 Start/End Date: Oct 2013–Sep 2014 Indication: Plaque psoriasis Route of Admin: Topical MOA: Vitamin D analog ClinicalTrials.gov Identifier: NCT01989429
H3C H3C
F F N H F
F F
H
HO
32. Polmacoxib (CG100649)
O
OH
32
Sponsor: Crystal Genomics MW/c Log D: 361.39/2.35 CAS#: 301692-76-2 Start/End Date: Mar 2013–Dec 2013 Indication: Osteoarthritis Route of Admin: Oral, 2 mg MOA: Cyclooxygenase 2 inhibitor ClinicalTrials.gov Identifier: NCT01765296
O H3C
O S NH 2
O
H3C
F O
33. Reparixin (DF-1681)33
Sponsor: Dompe´ MW/c Log D: 283.39/0.47 CAS#: 266359-83-5 Start/End Date: Jul 2012–May 2014 Indication: Islet transplantation in diabetes mellitus type 1 Route of Admin: iv MOA: CXCR1/CXCR2/IL-8 antagonist ClinicalTrials.gov Identifier: NCT01817959
O
O S N H 3C H
CH3
O
CH3 CH3
Continued
34. Retagliptin (SP-2086)34
Sponsor: Jiangsu HengRui Medicine MW/c Log D: 464.36/1.73 CAS#: 1174122-54-3 Start/End Date: Apr 2013–Jan 2014 Indication: Type 2 diabetes mellitus Route of Admin: Oral, 50 mg, qd or bid MOA: Dipeptidyl peptidase IV inhibitor ClinicalTrials.gov Identifier: NCT01970046
F
F F
H3C
F
N
N
N
O
O
O
NH2
35. Selumetinib (ARRY-886)35
Sponsor: AstraZeneca MW/c Log D: 457.68/5.55 CAS#: 606143-52-6 Start/End Date: Sep 2013–Jul 2016 Indication: Non-small cell lung cancer with KRAS mutation Route of Admin: Oral, 75 mg, bid MOA: MEK inhibitor ClinicalTrials.gov Identifier: NCT01933932
Br
Cl
HO
O
F HN H N
N N CH3
O
36. Talazoparib (BMN-673)36
Sponsor: BioMarin MW/c Log D: 380.35/1.91 CAS#: 1207456-01-6 Start/End Date: Oct 2013–Jun 2016 Indication: BRCA mutated breast cancer Route of Admin: Oral, 1.0 mg, qd MOA: PARP-1/2 inhibitor ClinicalTrials.gov Identifier: NCT01945775
F F
F
N N
NH
N
H 3C N HN
F O
37. Tenofovir alafenamide (GS-7340)37
Sponsor: Gilead MW/c Log D: 476.47/2.20 CAS#: 379270-37-8 Start/End Date: Dec 2012–Sep 2014 Indication: HIV infection Route of Admin: Oral, 10 mg, qd MOA: Reverse transcriptase inhibitor ClinicalTrials.gov Identifier: NCT01780506
NH2 N N
H3C
N N O
O P O NH CH3
O
H3C
CH3
O
38. Tetrabenazine-d6 (SD-809)38 O
Sponsor: Auspex MW/c Log D: 323.46/3.43 CAS#: 1221885-59-1 O D Start/End Date: Jun 2013–Aug 2014 D Indication: Chorea D O Route of Admin: Oral, 6–12 mg D MOA: Vesicular monoamine transporter 2 inhibitor D D ClinicalTrials.gov Identifier: NCT01795859
CH3 CH3
N
39. Velcalcetide (AMG-416)39
Sponsor: Amgen MW/c Log D: 1016.19/ CAS#: 1262780-97-1 Start/End Date: Jul 2013–May 2015 Indication: Secondary hyperparathyroidism Route of Admin: iv MOA: Calcium-sensing receptor agonist ClinicalTrials.gov Identifier: NCT01785875
O H2N
H N
H2N
NH
O
H2N O
N H
H N
H2N
NH
O
H N
N H CH3 O NH H2N
H N
H2N
NH
O
H N O
N H
OH S H N
CH3 O
O N H
CH3
N H Continued
40. Venetoclax (ABT-199)40
Sponsor: AbbVie MW/c Log D: 868.44/7.87 CAS#: 1257044-40-8 Start/End Date: Dec 2013–Aug 2018 Indication: Chronic lymphocytic leukemia Route of Admin: Oral, 400 mg, qd MOA: Bcl-2 inhibitor ClinicalTrials.gov Identifier: NCT02005471
H3C
CH3
NH N
O
Cl
N N
O
HN O2N
O
S
H N O O
41. Veruprevir (ABT-450)41
Sponsor: AbbVie MW/c Log D: 765.88/0.87 CAS#: 1216941-48-8 Start/End Date: Aug 2012–Jan 2014 Indication: HCV infection Route of Admin: Oral, qd, with ritonavir MOA: NS3 protease inhibitor ClinicalTrials.gov Identifier: NCT01674725
N H 3C
O
N H N
N O
H N
N O
O
O O O S N H
42. Volasertib (BI-6727)42
Sponsor: Boehringer Ingelheim MW/c Log D: 618.81/1.72 CAS#: 755038-65-4 Start/End Date: Jan 2013–Jan 2016 Indication: Acute myeloid leukemia Route of Admin: iv MOA: Polo-like kinase-1 inhibitor ClinicalTrials.gov Identifier: NCT01721876
N O H3C
CH3
CH3
N
O
N
N N
N
O N H
N H
CH3
H3C
43. Zoptarelin Doxorubicin (AN-152)43
Sponsor: AEterna Zentaris MW/c Log D: 1893.01/2.44 CAS#: 139570-93-7 Start/End Date: Apr 2013–Dec 2015 Indication: Endometrial cancer Route of Admin: iv MOA: DNA topoisomerase II inhibitor ClinicalTrials.gov Identifier: NCT01767155
Glp-His-Trp-Ser-Tyr-D-Lys-Leu-Arg-Pro-Gly-NH2 O
O
OH
O OH
H3C
O
O H3C
OH O
HO NH2
O
NH O
O
434
Gregory T. Notte
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