Evofosfamide

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Evofosfamide
Names
Preferred IUPAC name
(1-Methyl-2-nitro-1H-imidazol-5-yl)methyl N,N′-bis(2-bromoethyl)phosphorodiamidate
Other names
TH-302; HAP-302
Identifiers
CAS Number
  • 918633-87-1 checkY
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:231678
ChEMBL
  • ChEMBL260046
ChemSpider
  • 10157061 checkY
KEGG
  • D10704 checkY
PubChem CID
  • 11984561
UNII
  • 8A9RZ3HN8W checkY
CompTox Dashboard (EPA)
  • DTXSID60238721 Edit this at Wikidata
InChI
  • InChI=1S/C9H16Br2N5O4P/c1-15-8(6-12-9(15)16(17)18)7-20-21(19,13-4-2-10)14-5-3-11/h6H,2-5,7H2,1H3,(H2,13,14,19) checkY
    Key: UGJWRPJDTDGERK-UHFFFAOYSA-N checkY
  • CN1C(=CN=C1[N+](=O)[O-])COP(=O)(NCCBr)NCCBr
Properties
Chemical formula
 C9H16Br2N5O4P
Molar mass 449.040 g·mol−1
Solubility in water
 6 to 7 g/L
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references
Chemical compound

Evofosfamide (INN,[1] USAN;[2] formerly known as TH-302) is a compound being evaluated in clinical trials for the treatment of multiple tumor types as a monotherapy and in combination with chemotherapeutic agents and other targeted cancer drugs.

This compound has been evaluated in the treatment of solid tumors, as a hypoxia-activated prodrug (HAPs), such chemical agents in low oxygen conditions undergo bio-reduction to yield cancer fighting cytotoxic breakdown products.

Many such agents have been developed, though this compound has been extensively studied, in preclinical and clinical studies.[3] [4]

Collaboration

Evofosfamide was developed by Threshold Pharmaceuticals Inc. In 2012, Threshold signed a global license and co-development agreement for evofosfamide with Merck KGaA, Darmstadt, Germany (EMD Serono Inc. in the US and Canada), which includes an option for Threshold to co-commercialize evofosfamide in the United States. Threshold is responsible for the development of evofosfamide in the soft tissue sarcoma indication in the United States. In all other cancer indications, Threshold and Merck KGaA are developing evofosfamide together.[5] From 2012 to 2013, Merck KGaA paid 110 million US$ for upfront payment and milestone payments to Threshold. Additionally, Merck KGaA covers 70% of all evofosfamide development expenses.[6]

Mechanism of prodrug activation and Mechanism of action (MOA) of the released drug

Evofosfamide is a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). Evofosfamide is activated by a process that involves a 1-electron (1 e−) reduction mediated by ubiquitous cellular reductases, such as the NADPH cytochrome P450, to generate a radical anion prodrug:

Evofosfamide is essentially inactive under normal oxygen levels. In areas of hypoxia, evofosfamide becomes activated and converts to an alkylating cytotoxic agent resulting in DNA cross-linking. This renders cells unable to replicable their DNA and divide, leading to apoptosis. This investigational therapeutic approach of targeting the cytotoxin to hypoxic zones in tumors may cause less broad systemic toxicity that is seen with untargeted cytotoxic chemotherapies.[8]

The activation of evofosfamide to the active drug Br-IPM and the mechanism of action (MOA) via cross-linking of DNA is shown schematically below:

Activation of eofosfamide to the active drug Br-IPM, and mechanism of action via cross-linking of DNA

Drug development history

Phosphorodiamidate-based, DNA-crosslinking, bis-alkylator mustards have long been used successfully in cancer chemotherapy and include e.g. the prodrugs ifosfamide and cyclophosphamide. To demonstrate that known drugs of proven efficacy could serve as the basis of efficacious hypoxia-activated prodrugs, the 2-nitroimidizole HAP of the active phosphoramidate bis-alkylator derived from ifosfamide was synthesized. The resulting compound, TH-281, had a high HCR (hypoxia cytotoxicity ratio), a quantitative assessment of its hypoxia selectivity. Subsequent structure-activity relationship (SAR) studies showed that replacement of the chlorines in the alkylator portion of the prodrug with bromines improved potency about 10-fold. The resulting, final compound is evofosfamide (TH-302).[9]

Synthesis

Evofosfamide can be synthesized in 7 steps.[10][11]

Formulation

The evofosfamide drug product formulation used until 2011 was a lyophilized powder. The current drug product formulation is a sterile liquid containing ethanol, dimethylacetamide and polysorbate 80. For intravenous infusion, the evofosfamide drug product is diluted in 5% dextrose in WFI.[12]

Diluted evofosfamide formulation (100 mg/mL evofosfamide, 70% ethanol, 25% dimethylacetamide and 5% polysorbate 80; diluted to 4% v/v in 5% dextrose or 0.9% NaCl) can cause leaching of DEHP from infusion bags containing PVC plastic.[13]

Clinical trials

Overview and results

Evofosfamide (TH-302) is currently being evaluated in clinical studies as a monotherapy and in combination with chemotherapy agents and other targeted cancer drugs. The indications are a broad spectrum of solid tumor types and blood cancers.

Evofosfamide clinical trials (as of 21 November 2014)[14] sorted by (Estimated) Primary Completion Date:[15]

Evofosfamide (TH-302) clinical trials in following indications:

Solid Tumors, Soft Tissue Sarcoma, Pancreatic Cancer/Pancreatic Adenocarcinoma/Pancreatic Neuroendocrine Tumors, Non-Small Cell Lung Cancer, Melanoma, Prostate Cancer, Kidney Cancer/Renal Cell Carcinoma, Liver Cancer/Hepatocellular Carcinoma, Myelogenous Leukemia/Lymphocytic Leukemia, Myelodysplastic Syndrome, Myelofibrosis, Multiple Myeloma, Glioma/Glioblastoma, Gastrointestinal Stromal Tumors

NCT Number /
Title		 Other IDs Start Date (Estimated) Primary Completion Date Recruitment Conditions Interventions Phases Enrollment (Patients) Sponsor / Collaborators
NCT00495144
A Phase I Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of TH-302 in Patients With Advanced Solid Tumors		 TH-CR-401 June 2007 December 2011 Completed Tumors, Hypoxia Drug: TH-302 Phase 1 129 Threshold Pharmaceuticals
NCT01149915
Study of Hypoxia-Activated Prodrug TH-302 to Treat Advanced Leukemias		 TH-CR-407 June 2010 August 2013 Completed Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, High-risk Myelodysplastic Syndrome, Chronic Lymphocytic Leukemia, Advanced Myelofibrosis Drug: TH-302 Phase 1 40 Threshold Pharmaceuticals
NCT01144455
Study of the Safety and Efficacy of TH-302 in Combination With Gemcitabine Compared With Gemcitabine Alone in Previously Untreated Patients With Pancreatic Adenocarcinoma 		TH-CR-404 June 2010 August 2013 Completed Pancreatic Adenocarcinoma Drug: Gemzar (Gemcitabine), Drug: TH-302, Drug: TH-302 Phase 2 165 Threshold Pharmaceuticals, PRA Health Sciences
Results:

30 March 2012[16][17]

  • The study met its primary efficacy endpoint with a median increase in progression-free survival (PFS) from 3.6 months to 5.6 months in the pooled patients treated with TH-302 (at 240 mg/m2 or 340 mg/m2) in combination with gemcitabine compared to gemcitabine alone.
  • In addition, a dose response was identified with the greatest efficacy in the higher 340 mg/m2 group with a median PFS of 6.0 months.

18 November 2014[18]

  • gemcitabine alone (N=69): Median PFS of 3.6 months, median OS of 6.9 months.
  • gemcitabine + TH-302 240 mg/m2 (N=71): Median PFS of 5.6 months, median OS of 8.7 months.
  • gemcitabine + TH-302 340 mg/m2 (N=74): Median PFS of 6.0 months, median OS of 9.2 months.
NCT00742963
Dose-Escalation Study of TH-302 in Combination With Doxorubicin to Treat Patients With Advanced Soft Tissue Sarcoma		 TH-CR-403 August 2008 September 2013 Completed Soft Tissue Sarcoma Drug: TH-302 Phase 1, Phase 2 102 Threshold Pharmaceuticals
Results:

15 November 2012, Results for overall study population (N=91)[19][20]

  • Median progression free survival of 6.7 months.
  • Median overall survival of 21.5 months.

10 October 2014, Results for overall study population (N=91)[21]

  • Median progression free survival of 6.5 months.
  • Median overall survival of 21.5 months.
NCT00743379
Dose-Escalation Study of TH-302 in Combination With A) Gemcitabine or B) Docetaxel or C) Pemetrexed to Treat Advanced Solid Tumors		 TH-CR-402 August 2008 September 2013 Completed Non-Small Cell Lung Cancer, Prostate Cancer, Pancreatic Cancer Drug: TH-302 Phase 1, Phase 2 71 Threshold Pharmaceuticals
Results:

12 October 2010[22]

  • In the gemcitabine treatment arm, 43 patients with advanced or metastatic pancreatic cancer were treated: Median progression-free survival (PFS) was 6.4 months and median overall survival (OS) was 11.4 months.
  • In the TH-302 plus docetaxel or pemetrexed treatment arms of the trial, 32 patients with non-small cell lung cancer were treated: Median PFS was 4.2 months.

24 January 2011[23][24]

  • In the gemcitabine plus TH-302 treatment arms, 47 patients with advanced or metastatic pancreatic cancer were treated: Median progression free survival was 5.9 months and median overall survival was 8.5 months.

18 November 2014[25][26]

  • In the TH-302 plus pemetrexed treatment arm of the trial, 18 patients with non-small cell lung cancer were treated: Median PFS was 7.0 months. Median overall survival was 14.9 months.
NCT01497444
Sorafenib Tosylate and Hypoxia-Activated Prodrug TH-302 in Treating Patients With Advanced Kidney Cancer or Liver Cancer That Cannot Be Removed By Surgery		 TH-IST-4004, N1153, NCCTG-N1153, CDR0000720022, NCI-2012-00095, U10CA031946 May 2012 January 2014 Recruiting Kidney Cancer, Liver Cancer Drug: hypoxia-activated prodrug TH-302, Drug: sorafenib tosylate, Genetic: protein analysis, Other: laboratory biomarker analysis Phase 1, Phase 2 48 North Central Cancer Treatment Group, National Cancer Institute (NCI), Alliance for Clinical Trials in Oncology, Cancer and Leukemia Group B, American College of Surgeons, Threshold Pharmaceuticals
NCT01440088
A Trial of TH-302 in Combination With Doxorubicin Versus Doxorubicin Alone to Treat Patients With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma		 TH-CR-406 / SARC021 September 2011 June 2014 Active, not recruiting Soft Tissue Sarcoma Drug: TH-302 in Combination with Doxorubicin, Drug: Doxorubicin Phase 3 620 Threshold Pharmaceuticals, Sarcoma Alliance for Research through Collaboration (SARC)
Results:

18 September 2014[27]

  • Final phase 3 results available in 2015.

22 September 2014[28]

  • The planned interim efficacy and safety analyses has been completed: The trial will continue as planned to its natural conclusion.
  • The estimated primary completion date has been revised to the latter half of 2015.

3 November 2014[29]

  • Primary analysis of overall survival expected to be conducted in the first quarter of 2016.
NCT01381822
Dose-Escalation Study of TH-302 in Combination With Sunitinib to Treat Patients With Advanced Renal Cell Carcinoma, Gastrointestinal Stromal Tumors and Pancreatic Neuroendocrine Tumors		 TH-CR-410 June 2011 June 2014 Active, not recruiting Advanced Renal Cell Carcinoma, Gastrointestinal Stromal Tumors, Pancreatic Neuroendocrine Tumors Drug: TH-302 Phase 1 58 Threshold Pharmaceuticals
NCT01833546
A Japanese Phase 1 Trial of TH-302 in Subjects With Solid Tumors and Pancreatic Cancer		 EMR200592-002 April 2013 January 2015 Active, not recruiting Solid Tumor, Pancreatic Cancer Drug: TH-302 monotherapy, Drug: TH-302, Drug: Gemcitabine Phase 1 20 Merck KGaA, Threshold Pharmaceuticals
NCT02020226
A Cardiac Safety Study of TH-302 in Patients With Advanced Solid Tumors		 TH-CR-414 November 2013 January 2015 Recruiting Solid Tumors Drug: TH-302 Phase 1 40 Threshold Pharmaceuticals
NCT02076230
A Phase 1 TH-302 Mass Balance Trial		 EMR200592-007, 2013-003950-25 February 2014 March 2015 Active, not recruiting Solid Tumors Drug: [14C] TH-302 (Label 1), Drug: [14C] TH-302 (Label 2), Drug: Unlabeled TH-302 Phase 1 10 Merck KGaA, Threshold Pharmaceuticals
NCT01522872
Open-label Study of TH-302 and Dexamethasone With or Without Bortezomib in Subjects With Relapsed/Refractory Multiple Myeloma		 TH-CR-408 February 2012 June 2015 Recruiting Multiple Myeloma Drug: TH-302, Drug: TH-302, Drug: TH-302 and bortezomib Phase 1, Phase 2 60 Threshold Pharmaceuticals
NCT01864538
A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma		 TH-CR-413 May 2013 June 2015 Recruiting Metastatic Melanoma Drug: TH-302 Phase 2 40 Threshold Pharmaceuticals
NCT01403610
Safety and Efficacy Study of TH-302 CNS Penetration in Recurrent High Grade Astrocytoma Following Bevacizumab		 TH-IST-4003, CTRC 11-24 June 2011 July 2015 Recruiting High Grade Glioma Drug: TH-302, Drug: Placebo Phase 2 34 The University of Texas Health Science Center at San Antonio
Results:

30 May 2014[30][31]

  • Median progression-free survival (PFS) of 3.1 months on combination therapy vs. 2.4 months on prior single-agent bevacizumab.

17 November 2014[32]

  • Median progression-free survival (PFS) of 2.8 months on bevacizumab/TH-302 combination therapy (N=22).
  • Median overall survival of 4.6 months on bevacizumab/TH-302 combination therapy (N=22).
NCT01721941
TH-302 Plus Doxorubicin Delivered by Trans-Arterial Chemoembolization (TACE) in Patients With Hepatocellular Carcinoma		 TH302 TACE December 2014 December 2015 Not yet recruiting Hepatocellular Carcinoma Drug: Phase I Dose level -1, Drug: Phase I dose level 1, Drug: Phase I Dose level 2, Drug: Phase I Dose level 3 Phase 1 20 Scripps Clinic Cancer Center, Threshold Pharmaceuticals
NCT01746979
Clinical Trial Testing TH-302 in Combination With Gemcitabine in Previously Untreated Subjects With Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma		 MAESTRO, EMR 200592-001, 2012-002957-42 December 2012 February 2016 Active, not recruiting Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma Drug: TH-302, Drug: Gemcitabine, Drug: Placebo (5 percent dextrose - D5W) Phase 3 660 EMD Serono, Threshold Pharmaceuticals
Results:

3 November 2014[33]

  • Target enrollment of 660 patients completed.
  • Top-line data anticipated in 2016.

18 November 2014[34]

  • Top-line data anticipated in Q1/2016.
NCT02047500
Phase I TH-302 Plus Gemcitabine Plus Nab-Paclitaxel in Pancreatic Cancer		 EMR200592-006 January 2014 June 2016 Recruiting Pancreatic Cancer Drug: TH-302, Drug: Nab-paclitaxel, Drug: Gemcitabine Phase 1 48 EMD Serono, Threshold Pharmaceuticals
NCT02093962
Study of TH-302 or Placebo in Combination With Pemetrexed in Patients With Non-squamous Non-small Cell Lung Cancer		 TH-CR-415 March 2014 July 2016 Recruiting Non-small Cell Lung Cancer Drug: TH-302 combination with pemetrexed, Drug: Matched placebo in combination with pemetrexed Phase 2 440 Threshold Pharmaceuticals, EMD Serono
Results:

18 November 2014[35]

  • Expect enrollment to be completed end of 2015.
NCT02255110
A Japanese Trial of TH-302 in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma		 EMR200592-008 October 2014 October 2016 Recruiting Soft Tissue Sarcoma Drug: TH-302, Drug: Doxorubicin Phase 2 46 Merck KGaA, Threshold Pharmaceuticals
NCT01485042
Dose Escalation Study of Pazopanib Plus TH-302		 PATH, TH-IST-4001, Pro00031123 December 2011 December 2016 Active, not recruiting Solid Tumors Drug: Pazopanib and TH-302 Phase 1 50 Herbert Hurwitz, MD, National Comprehensive Cancer Network, GlaxoSmithKline, Threshold Pharmaceuticals, Duke University
EudraCT: 2014-004072-30
A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) previously untreated 		GETNE-1408, EMR 200592-012 January 2015 Ongoing Metastatic pancreatic neuroendocrine tumors (pNET) Drug: TH-302 in combination with sunitinib Phase 2 43 Grupo Español de Tumores Neuroendocrinos, MFAR, S.L., Spain
NCT02342379
TH-302 in Combination With Bevacizumab for Glioblastoma		 TH-IST-4008, CTRC 12-0105 February 2015 February 2017 Not yet recruiting Glioblastoma Drug: Bevacizumab and TH-302 Phase 2 33 The University of Texas Health Science Center at San Antonio
Note: Results based on Response Evaluation Criteria in Solid Tumors (RECIST) assessments are not shown.

Soft tissue sarcoma

Both, evofosfamide and ifosfamide have been investigated in combination with doxorubicin in patients with advanced soft tissue sarcoma. The study TH-CR-403 is a single arm trial investigating evofosfamide in combination with doxorubicin.[36] The study EORTC 62012 compares doxorubicin with doxorubicin plus ifosfamide.[37] Doxorubicin and ifosfamide are generic products sold by many manufacturers.

The indirect comparison of both studies shows comparable hematologic toxicity and efficacy profiles of evofosfamide and ifosfamide in combination with doxorubicin. However, a longer overall survival of patients treated with evofosfamide/doxorubicin (TH-CR-403) trial was observed. The reason for this increase is probably the increased number of patients with certain sarcoma subtypes in the evofosfamide/doxorubicin TH-CR-403 trial, see table below.

However, in the Phase 3 TH-CR-406/SARC021 study (conducted in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC)), patients with locally advanced unresectable or metastatic soft tissue sarcoma treated with evofosfamide in combination with doxorubicin did not demonstrate a statistically significant improvement in OS compared with doxorubicin alone (HR: 1.06; 95% CI: 0.88 - 1.29).[citation needed]

Comparison of ifosfamide/doxorubicin with evofosfamide/doxorubicin in soft tissue sarcoma
Baseline Characteristics Study ID NCT00061984
Phase 3 trial EORTC 62012[38]		 NCT01440088
Phase 2 trial TH-CR-403[39]
Drug 1 Doxorubicin 75 mg/m2 Day 1
or as a 72-hour continuous i.v. infusion		 Doxorubicin 25 mg/m2 Days 1-3 Doxorubicin 75 mg/m2 Day 1
Drug 2 Ifosfamide 2.5 g/m2 Days 1-4 Evofosfamide 300 mg/m2 Days 1, 8
Drug 3 Pegfilgrastim 6 mg s.c. Day 5 Growth Factor Day 8 or Day 9
Patients N=228 N=227 N=91
Median number of cycles 5 cycles 6 cycles 7 cycles (N = 91)
+ 10 maintenance cycles (n = 48)
Number of patients with sarcoma subtype
Leiomyosarcoma or Liposarcoma		 35% 40% 52%
Efficacy Median Progression-free survival 4.6 months 7.4 months 6.5 months
Median Overall survival (OS) 12.8 months 14.3 months 21.5 months
Median OS, Leiomyosarcoma patients 31.9 months
Median OS, Liposarcoma patients 32.9 months
Hematologic Toxicity Grade 3/4 Neutropenia 37% 42% 31%
Grade 3/4 Febrile Neutropenia 13% 46% 8%
Grade 3/4 Thrombocytopenia < 1% 34% 32%
Grade 3/4 Anemia 4% 35% 36%
Grade 3/4 Leucopenia 18% 43% N/A

Metastatic pancreatic cancer

Both, evofosfamide and protein-bound paclitaxel (nab-paclitaxel) have been investigated in combination with gemcitabine in patients with metastatic pancreatic cancer. The study TH-CR-404 compares gemcitabine with gemcitabine plus evofosfamide.[40] The study CA046 compares gemcitabine with gemcitabine plus nab-paclitaxel.[41] Gemcitabine is a generic product sold by many manufacturers.

The indirect comparison of both studies shows comparable efficacy profiles of evofosfamide and nab-paclitaxel in combination with gemcitabine. However, the hematologic toxicity is increased in patients treated with evofosfamide/gemcitabine (TH-CR-404 trial), see table below.

In the Phase 3 MAESTRO study, patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with evofosfamide in combination with gemcitabine did not demonstrate a statistically significant improvement in overall survival (OS) compared with gemcitabine plus placebo (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.71 - 1.01; p=0.0589).[citation needed]

Comparison of gemcitabine/nab-paclitaxel with gemcitabine/evofosfamide in metastatic pancreatic adenocarcinoma
Baseline Characteristics Study ID NCT00844649
Phase 3 trial CA046[42]		 NCT01144455
Phase 2 trial TH-CR-404[43]
Drug 1 Gemcitabine
1 g/m2
Schedule A		 Gemcitabine
1 g/m2
Schedule B		 Gemcitabine
1 g/m2
Schedule B		 Gemcitabine
1 g/m2
Schedule B		 Gemcitabine
1 g/m2
Schedule B
Drug 2 --- nab-Paclitaxel
125 mg/m2
Schedule B		 --- Evofosfamide
240 mg/m2
Schedule B		 Evofosfamide
340 mg/m2
Schedule B
Drug 3 15% of patients received
growth factors		 26% of patients received
growth factors		 Optional: Growth factors Optional: Growth factors Optional: Growth factors
Patients [N] 430 431 69 71 74
Efficacy Median Progression-free survival [months] 3.7 5.5 3.6 5.6 6.0
Median Overall survival [months] 6.7 8.5 6.9 (1) 8.7 (1) 9.2 (1)
Hematologic Toxicity Grade 3/4 Neutropenia [%] 27 38 17 34 43
Grade 3/4 Febrile Neutropenia [%] 1 3 N/A N/A N/A
Grade 3/4 Thrombocytopenia [%] 9 13 12 30 55
Grade 3/4 Anemia [%] 12 13 29 34 43
Grade 3/4 Leucopenia [%] 16 31 N/A N/A N/A
Schedule A: Weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles)

Schedule B: On days 1, 8 and 15 every 4 weeks
(1) statistically not significant

Nasopharyngeal Carcinoma

Oxygen deficient conditions are linked to tumor progression throughout the body and poses an issue in cancer treatments such as chemotherapy and radiation.[44] Hypoxia-activated prodrugs (HAPs) function in hypoxic conditions and inhibit the growth of tumor cells.[45] Evofosfamide is a HAP that targets tumor progression in nasopharyngeal carcinoma (NPC) tissues by inhibitng the overexpression of hypoxia-inducible factor-1α (HIF-1α).[46]

In this study , the efficacy of Evofosfamide along with cisplastin (DDP) in blocking cell progression was measured. "The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 μmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (γH2AX) (a marker of DNA damage) expression increased while HIF-1α expression suppressed after evofosfamide treatment under hypoxic conditions".[47] These findings allow for evidence for Evofosfamide to be pushed towards clinical trials to further investigate the potential to be developed as an FDA approved anticancer drug.

Drug development risks

Risks published in the quarterly/annual reports of Threshold and Merck KGaA that could affect the further development of evofosfamide (TH-302):

The evofosfamide formulation that Threshold and Merck KGaA are using in the clinical trials was changed in 2011[48] to address issues with storage and handling requirements that were not suitable for a commercial product. Additional testing is ongoing to verify if the new formulation is suitable for a commercial product. If this new formulation is also not suitable for a commercial product another formulation has to be developed and some or all respective clinical phase 3 trials may be required to be repeated which could delay the regulatory approvals.[49]

Even if Threshold/Merck KGaA succeed in obtaining regulatory approvals and bringing evofosfamide to the market, the amount reimbursed for evofosfamide may be insufficient and could adversely affect the profitability of both companies. Obtaining reimbursement for evofosfamide from third-party and governmental payors depend upon a number of factors, e.g. effectiveness of the drug, suitable storage and handling requirements of the drug and advantages over alternative treatments.

There could be the case that the data generated in the clinical trials are sufficient to obtain regulatory approvals for evofosfamide but the use of evofosfamide has a limited benefit for the third-party and governmental payors. In this case Threshold/Merck KGaA could be forced to provide supporting scientific, clinical and cost effectiveness data for the use of evofosfamide to each payor. Threshold/Merck KGaA may not be able to provide data sufficient to obtain reimbursement.[50]

Each cancer indication has a number of established medical therapies with which evofosfamide will compete, for example:

Threshold relies on third-party contract manufacturers for the manufacture of evofosfamide to meet its and Merck KGaA's clinical supply needs. Any inability of the third-party contract manufacturers to produce adequate quantities could adversely affect the clinical development and commercialization of evofosfamide. Furthermore, Threshold has no long-term supply agreements with any of these contract manufacturers and additional agreements for more supplies of evofosfamide will be needed to complete the clinical development and/or commercialize it. In this regard, Merck KGaA has to enter into agreements for additional supplies or develop such capability itself. The clinical programs and the potential commercialization of evofosfamide could be delayed if Merck KGaA is unable to secure the supply.[52]

History

Date Event
Jun 2005 Threshold files evofosfamide (TH-302) patent applications in the U.S.[53]
Jun 2006 Threshold files an evofosfamide (TH-302) patent application in the EU and in Japan[54]
Sep 2011 Threshold starts a Phase 3 trial (TH-CR-406) of evofosfamide in combination with doxorubicin in patients with soft tissue sarcoma
Feb 2012 Threshold signs an agreement with Merck KGaA to co-develop evofosfamide
Apr 2012 A Phase 2b trial (TH-CR-404) of evofosfamide in combination with gemcitabine in patients with pancreatic cancer meets primary endpoint
Jan 2013 Merck KGaA starts a global Phase 3 trial (MAESTRO) of evofosfamide in combination with gemcitabine in patients with pancreatic cancer
Dec 2015 two Phase 3 trials fail, Merck will not apply for a license[citation needed]

References

  1. ^ WHO Drug Information; Recommended INN: List 73
  2. ^ Adopted Names of the United States Adopted Names Council
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  6. ^ "Threshold Pharmaceuticals Form 8-K from 3 Nov 2014". Archived from the original on 6 November 2014. Retrieved 5 November 2014.
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  11. ^ Synthetic route Reference: International patent application WO2007002931A2
  12. ^ FDA Advisory Committee Briefing Materials Available for Public Release, TH-302: Pediatric oncology subcommittee of the oncologic drugs advisory committee (ODAC) meeting, December 4, 2012
  13. ^ "AAPS 2014 – Measurement of Diethylhexyl Phthalate (DEHP) Leached from Polyvinyl Chloride (PVC) Containing Plastics by Infusion Solutions Containing an Organic Parenteral Formulation – Poster W4210, Nov 5, 2014" (PDF). Archived from the original (PDF) on April 3, 2015. Retrieved March 11, 2015.
  14. ^ ClinicalTrials.gov
  15. ^ The Primary Completion Date is defined as the date when the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome.
  16. ^ "Detailed Results From Positive Phase 2b Trial of TH-302 in Pancreatic Cancer at AACR Annual Meeting - Press release from 30 March 2012". Archived from the original on 25 October 2014. Retrieved 25 October 2014.
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