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zdy1398

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[交流] 【求助】NPI-0052的临床二期资料

npi-0052是从海洋微生物次级代谢产物中弄出来的一个活性化合物，抗肿瘤的

2009年才进入临床二期，可是我听说它在临床二期失败了，研发这个药物的公司已经放弃这个药物了，却怎么也找不到有关它临床2期实验失败的消息！！

我给那个公司的教授发过电子邮件，想确认此事，可他不回，请问一下这个东西是保密的吗？

我能找到在2009年6月份asco年会上有人介绍npi-0052临床1期成功的消息


简言之，我想知道这个NPI-0052在临床二期到底是不是失败了？？？？请给个链接

谢谢！！！
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nkbeholder

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zdy1398(金币+5,VIP+0): 12-20 11:38
没有二期的消息。


Drug: Salinosporamide A
Synonyms: NPI 0052; NPI-0052
Chemical Name: (1R,4R,5S)-4-(2-Chloroethyl)-1-((S)-((S)-cyclohex-2- enyl)(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo(3.2.0)heptane-3,7- dione
Molecular Formula: C15H20ClNO4
Therapeutic Class:

Antineoplastic Agents
Antineoplastics
Mechanism of Action:

Proteasome inhibitors
Multienzyme complex inhibitors
Multiprotein complex inhibitors
Enzyme inhibitors
Multienzyme complex modulators
Macromolecular substance inhibitors
Multiprotein complex modulators
Enzyme modulators
Macromolecular substance modulators
Originator Company: Nereus Pharmaceuticals (USA)
Parent Company: Nereus Pharmaceuticals

Highest Phase: Phase I

Development Status:

Phase I, Australia, Cancer
Phase I, Estonia, Cancer
Phase I, USA, Lymphoma
Phase I, USA, Multiple myeloma
Phase I, Australia, Solid tumours
Phase I, USA, Solid tumours
Introduction:
Salinosporamide A is a small molecule proteasome inhibitor which is being evaluated by Nereus Pharmaceuticals as a treatment for multiple myeloma, lymphomas and solid tumours. By inhibiting proteasomes, salinosporamide A prevents the breakdown of proteins involved in signal transduction, which blocks growth and induces apoptosis in cancer cells. Salinosporamide A was discovered during the fermentation of Salinospora tropica, a marine Gram-positive actinomycete. Phase I trials with salinosporamide A are underway in the US, Australia and Estonia for the treatment of solid tumours, lymphomas, and multiple myeloma.

Nereus is seeking collaborators interested in co-developing salinosporamide A.

Key development milestones
In April 2008, Nereus initiated a phase Ib study of IV administered salinosporamide A in combination with oral vorinostat in patients with solid tumours in Australia (NCT00667082). The open-label study will enrol approximately 40 patients with advanced non-small cell lung cancer, pancreatic cancer or melanoma for whom standard approved therapy is not available and will investigate the maximum tolerated dose (MTD) and recommended dose for the combined agents for phase II development. Interim data has been reported/1/ /2/.

A US-based phase I trial in 35 patients with advanced multiple myeloma was initiated by Neureus Pharmaceuticals in April 2007 in the US(NCT00461045). This dose-escalation study will assess the safety, toxicity, and maximum tolerated dose of salinosporamide A when administered by IV-injection. A total of 10 patients have been treated to date at doses ranging from 0.025-0.075 mg/m sup(2); the MTD has not yet been reached. Dose escalation continues to define a recommended phase II dose. Dependent on the degree of efficacy seen in this trial, Nereus expects to pursue an accelerated registration strategy in multiple myeloma. Interim results have been reported/3/ /4/.

Nereus initiated a US-based phase I trial in 50 patients with advanced solid tumors or lymphoma in May 2006 (NCT00396864). This dose- escalation study will assess the safety, toxicity, and maximum tolerated dose of NPI 0052 when administered by IV-injection. Subsequent to determining the maximum tolerated dose, 20 additional patients will be entered to gain preliminary data on efficacy. The trial is expected to reach completion in March 2009/5/ /6/.

Nereus is also conducting another phase I trial of salinosporamide A in 50 patients with advanced malignancies including solid tumors, lymphomas, leukemias and multiple myeloma in Australia and Estonia (NCT00629473). The study is anticipated to reach completion by September 2009.

Combination of salinosporamide A and lenalidomide induced synergistic activity against multiple myeloma (MM) cell lines in vitro , and inhibited tumour growth and prolonged survival in mice bearing MM cells/7/.

In August 2007, Nereus raised $US45 million from a series D-2 financing. The proceeds will be used to complete phase I trials of salinosporamide A and begin phase II trials with the compound/8/.

Nereus in conjunction with Dana-Farber Cancer Institute investigated the in vitro effect of salinosporamide A alone and in combination with bortezomib against Waldenstrom's macroglobulinaemia cell lines. The company's preclinical programme for salinosporamide A evaluated the effect of salinosporamide A in reversal of B cell non-Hodgkin's lymphomas resistance to apoptosis/9/ /10/.

Nereus is also investigating an oral formulation of salinosporamide A. Preclinical trials with the formulation have been conducted.

Pharmacology Overview:
Antimicrobial activity:
  
  Pharmacodynamics:
  Inhibits the 20S proteasome; efficacious in animal models of myeloma, colon, pancreatic and lung cancer when administered orally or intravenously; in patients with lymphomas or solid tumours appears to produce dose-dependent pharmacological effect below the MTD; regulates sensitivity of lymphoma cells to TRAIL-induced apoptosis via inhibition of the metastasis-induced transcription factor Snail and induction of Raf-1 kinase inhibitor protein; shows synergistic activity with lenalidomide against multiple myeloma in vitro and in vivo; synergy in vitro with histone deacetylase inhibitors
  Immunogenicity:
  
  Mechanism of action:
  Proteasome inhibitors
   Multienzyme complex inhibitors
   Multiprotein complex inhibitors
   Enzyme inhibitors
   Multienzyme complex modulators
   Macromolecular substance inhibitors
   Multiprotein complex modulators
   Enzyme modulators
   Macromolecular substance modulators
  Activity versus parent drug: unspecified parent

Clinical Overview:
Route(s) of Administration: IV
  Administration Freq.(per day):
  Drug Interactions:
  Unknown. Salinosporamide in combination with vorinostat demonstrates no increase in toxicity and does not appear to affect the individual pharmacokinetics of either drug

Adverse Events:
Clinical: in a phase I trial of salinosporamide A in patients with solid tumour, lymphoma, leukaemia or myeloma diagnoses failing after standard therapies, the most common adverse events reported were fatigue, parosmia/dysgeusia, transient peri-infusion site pain, lymphopenia, headaches, dizziness/unsteady gait, closed-eye visuals and cognitive changes. Peripheral neuropathy, neutropenia and thrombocytopenia did not appear to be induced. The study has enrolled 48 patients who are receiving salinosporamide A intravenously on a weekly or twice weekly arm in the dose escalation portion of this study/11/.
A maximum tolerated dose (MTD) has not been reached after dosing with IV salinosporamide A ranging from 0.025-0.075 mg/m sup(2) in a phase I trial in patients with multiple myeloma. Interim results have demonstrated no significant drug-related toxicity and no peripheral neuropathy or myelosupression has been seen in 41 cycles in patients to date/3/.
An MTD has not been reached after dosing with IV salinosporamide A ranging from 0.0125-0.375 mg/m sup(2) in a phase I trial in patients with solid tumours or lymphomas. The most common adverse events included fatigue, nausea, constipation, and back pain. Serious adverse events potentially related to the study drug included MRSA sepsis and renal failure in 1 patient (treated at 0.1 mg/m sup(2)) and grade 4 neutropenia in 1 patient (treated at 0.112mg/m sup(2)). Apart from these two events, drug-related adverse events have been unremarkable at the highest dose tested/12/ /5/.
Preliminary results from a phase I trial in 22 patients with solid tumours, lymphoma, or leukaemia showed salinosporamide A (0.1 mg/m sup(2) to 0.55 mg/m sup(2)) did not reach a maximum tolerated dose. The adverse event profile was tolerable, with the most common drug- related adverse events being fatigue, transient peri-infusion site arm discomfort, and lymphopenia/13/.

Preclinical: in an in vivo mouse experiment, a single IV dose of NPI 0052 of 0.25 mg/kg or five consecutive daily IV doses of salinosporamide A of 0.1 mg/kg was well tolerated/14/.
Drug Interactions:
Interim results from a phase I study assessing the combination of IV NPI 0052 (0.7 mg/m sup(2)) and oral vorinostat in 20 patients with refractory melanoma, pancreatic carcinoma or NSCLC demonstrated the regimen to be tolerable and did not result in an increase in toxicity as compared with the drugs administered individually. Seven of 14 evaluated patient demonstrated regressions in tumour measurements, and the most anti-tumour activity was seen in patients with metastatic melanoma. Pharmacokinetic (PK) data demonstrated a t sub(1/2) of < 15 min for NPI 0052 and large volumes of distribution (V sub(z )= 73.9 +- 44.7 L and V sub(ss )= 80.7 +- 53.6 L), which did not seem to be dose dependent. The PK parameters of vorinostat were in agreement with published data (t sub(1/2) of 1.69 +- 0.86 hours and V sub(z/F) of 1040.1 +- 458.3 L). Proteasome inhibition assays showed dose dependent inhibition of the chymotrypsin-like proteasome activity of up to 78%. The most commonly reported adverse events were nausea, vomiting, constipation, diarrhoea and fatigue. NPI 0052 was administered intravenously on a weekly (days 1, 8 and 15) schedule dose escalation, in combination with vorinostat 300 mg orally on the first 16 days of each 28 day cycle. The dose of NPI 0052 was escalated from 0.15 mg/m sup(2) to 0.7 mg/m sup(2)/1/.

Pharmacokinetics:
IV-injection administered salinosporamide A (0.025-0.75 mg/m sup(2)) demonstrated a rapid elimination half-life of approximately 3-4 minutes with clearance between 8-21 mL/min and a volume of distribution of 44-99 L from interim results of a phase I trial in patients with relapsed or refractory multiple myeloma. No change in PK was observed comparing the first and second injection. Proteasome inhibition in whole blood suggested drug-dependent cytotoxic T lymphocytes (CTL) inhibition, with up to 28% inhibition observed/3/.
IV salinosporamide A (0.0125-0.375 mg/m sup(2)) demonstrated an elimination half-life of approximately 2-5 minutes, a clearance of 5.5-15 mL/min, and a volume of distribution of 16.5-103.5L in results from a phase I trial in patients with lymphomas or solid tumours/12/ /5/.
Pharmacodynamics (Cancer):
Clinical
Salinosporamide A appeared to produce a dose-dependent pharmacological effect at doses below the maximum tolerated dose (MTD) in preliminary results from a phase I trial in patients wtih lymphomas or solid tumours/5/.
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Preclinical
Salinosporamide A induced prolonged inhibition of all three 20S proteasome activities in established multiple myeloma (MM.1S) tumour xenografts. In the study, SCID male mice were treated with salinosporamide A, 0.15 mg/kg, IV approximately four weeks after inoculation with 5 x 10 sup(6) MM.1S tumour cells. Proteasome inhibition was assessed after a single treatment with salinosporamide A (on day 1) or three treatments (on days 1, 4 and 8). For efficacy studies, mice were treated with salinosporamide A twice a week for three weeks. Inhibition of proteasome activity was detected as early as 10 mins in the liver, lung. spleen, kidney and packed whole blood (PWB). Proteasome activity recovered within 24h of single or three IV treatments in these organs, but not in tumours or PWB. There was no significant proteasome inhibtion in the brain. In efficacy studies, CT-L, C-L and T-L activities were inhibited by 70-80% at 1h post third dose and the anti-tumour activity of salinosporamide A was associated with significant proteasome inhibition in the tumours/15/.
Combination of salinosporamide A and lenalidomide significantly induced synergistic activity in vitro against multiple myeloma cell lines. This apoptotic effect was associated with: activation of caspases (8, 9, and 3), poly (ADP-ribose) polymerase (PARP), BH-3 protein BIM; induction of c-Jun-NH2-terminal kinase; suppression of chymotrypsin-like, caspase-like and trypsin-like proteolytic activities; and inhibition of migration of MM cells and angiogenesis, and NF-kappa B signalling. In mouse bearing multiple myeloma cells (MM.1S), a low dose combination salinosporamide A (0.15 mg/kg) and lenalidomide (2.5 or 5.0 mg/kg) significantly inhibited tumour growth (P<0.03), and prolonged survival (4-5 months, P = 0.001). Immunohistochemical data of multiple myeloma tumours excised from mice receiving the combination showed growth inhibition, apoptosis, and a decrease in associated angiogenesis/7/.
In vitro data indicated that salinosporamide A regulates the sensitivity of B-cell non-Hodgkin's lymphoma (B-NHL) cells to apoptosis induced by tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) via inhibition of the metastasis-inducer transcription factor Snail and induction of Raf-1 kinase inhibitor protein (RKIP). Investigation in vitro in the Burkitt's lymphoma cell line Ramos showed that overexpression of RKIP sensitised the cells to TRAIL apoptosis. In Ramos cells exposed to salinosporamide A, Snail expression was significantly downregulated and RKIP was upregulated. In Ramos cells exposed to small interfering RNA Snail, RKIP and sensitisation to TRAIL apoptosis were upregulated, whereas ectopic expression of Snail resulted in repression of RKIP expression/16/.
Salinosporamide A inhibits the chymotrypsin-like (EC sub(50) = 2 nmol/ L) as well as the trypsin-like (EC sub(50 )~ 10 nmol/L) and peptidylglutamyl-peptide hydrolysing activities (EC sub(50 )~ 350 nmol/L) of rabbit 20S proteasomes. In LPS-stimulated RAW264.7 cells, salinosporamide A inhibited the synthesis of TNF- alpha. In an in vivo mouse study, preliminary results have shown that salinosporamide A exhibited a dose dependent inhibition of proteasome activity in whole blood lysates when administered either intravenously or orally. Various cell-based models have shown that salinosporamide A inhibits the activation of NF-kappa-B/14/ /17/.
In vitro, salinosporamide A induced apoptosis in bortezomib-resistant human multiple myeloma cells, without affecting normal cells. Salinosporamide A overcame resistance of multiple myeloma cells to melphalan, doxorubicin and dexamethasone, and showed anti-tumour activity in cells overexpressing P-glycoprotein and also in cells with altered topoisomerase-II activity. Salinosporamide A inhibited multiple myeloma cell growth induced both by adhesion to bone marrow stromal cells and by related cytokine secretion. In multiple myeloma cells, salinosporamide A induced apoptosis in the presence of interleukin-6 or insulin-like growth factor-1, reduced the cytoprotective effects of proteins Bc12 and Hsp27, and inhibited cell growth and survival mediated by NF-kappaB. Salinosporamide A stimulated multiple myeloma cell death by the following mechanisms: loss of mitochondrial membrane potential, superoxide generation, release of mitochondrial proteins cytochrome C/Smac, and activation of caspase-8/9/3. Salinosporamide A-induced apoptosis was neutralised by caspase inhibition. Salinosporamide A and bortezomib together produced synergistic apoptosis/18/.
Combination of salinosporamide A and bortezomib resulted in a synergistic apoptotic activity in vitro against multiple myeloma cells lines. This effect was associated with activation of caspases (8, 9 and 3) and poly (ADP-ribose) polymerase (PARP). In vivo, in human plasmocytoma xenograft mouse model, a low dose combination of salinosporamide A and bortezomib triggered synergistic inhibitory activity of tumour growth. The effect of the combination was attributed to the inhibition (by 30-40%) of all three (CT-L, C-L and T-L) proteasomal activities resulting in multiple cell myeloma apoptosis. Immunohistochemical data of multiple myeloma tumours excised from mice receiving combination of salinosporamide A and bortezomib showed growth inhibition, apoptosis, and a decrease in associated angiogenesis/19/.
In leukaemia cells, salinosporamide A was shown to synergistically interact with histone deacetylase inhibitors; results suggested that caspase-8 and oxidative stress dependent hyper-acetylation of histone-H3 contributed towards this synergistic interaction/20/.

Therapeutic Trials:
Cancer:
Salinosporamide A was associated with stable disease in a phase I trial in patients with lymphomas and solid tumours. In this study, patients were treated with salinosporamide A (0.0125-0.375 mg/m sup(2)) as an IV bolus for three weeks, in four-week cycles. The dose was escalated in cohorts of 3 patients dependent on observed adverse events. No clinical responses have been confirmed; however, stable disease has been observed in 7 patients for at least 2 months, including patients with hepatocellular carcinoma (6 cycles), adenoid cystic carcinoma (4 and 5 cycles), melanoma (4 cycles), colorectal cancer (6 cycles), ovarian cancer (4 cycles) and cervical cancer (12 cycles)/12/ /5/.
In a phase I trial of salinosporamide A in patients with hematologic and solid tumour malignancies, stable disease, regression or response, have been reported in those with mantle cell lymphoma, myeloma, Hodgkin's lymphoma, cutaneous marginal zone lymphoma, follicular lymphoma, sarcoma, prostate carcinoma and melanoma. The study has enrolled 48 patients who are receiving salinosporamide A intravenously on a weekly or twice weekly arm in the dose escalation portion of this study/11/.

References:
1. Millward M, Spear MA, et al. Clinical trial combining proteasome (NPI-0052) and HDAC (vorinostat) inhibition in melanoma, pancreatic, and lung cancer. 21st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. : abstr. A107, 15 Nov 2009. Available from: URL: http://www.aacr.org/home/scientists/ meetings--workshops/molecular-targets-and-cancer-therapeutics.aspx. (English).
2. Nereus Pharmaceuticals Inc. Nereus Pharmaceuticals Initiates Combination Clinical Trial for Proteasome Inhibitor NPI-0052 in Solid Tumors. Media Release. : 19 Apr 2008. Available from: URL: http:// www.nereuspharm.com. (English).
3. Richardson P, Hofmeister CC, et al. Phase 1 clinical trial of NPI-0052, a novel proteasome inhibitor in patients with multiple myeloma. 50th Annual Meeting and Exposition of the American Society of Hematology. : abstr. 2770, 7 Dec 2008. Available from: URL: http://www.hematology.org. (English).
4. Nereus Pharmaceuticals Inc. The Multiple Myeloma Research Consortium and Nereus Pharmaceuticals Initiate Clinical Trial Investigating NPI-0052 to Treat Multiple Myeloma. Media Release. : 17 Apr 2007. Available from: URL: http://www.nereuspharm.com. (English).
5. Kurzrock R, Hamlin P, et al. Results from phase 1 dose escalation study of the proteasome inhibitor NPI-0052 in aptients with solid tumors and lymphomas. 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. : 162, 22 Oct 2007. (English).
6. Nereus Pharmaceuticals Inc. Nereus Pharmaceuticals Initiates Phase I Clinical Trial for Anti-Cancer Proteasome Inhibitor. Media Release. : 15 May 2006. Available from: URL: http://www.nereuspharm.com. (English).
7. Chauhan D, Singh AV, et al. Combination of a novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vivo synergistic cytotoxicity in multiple myeloma. 50th Annual Meeting and Exposition of the American Society of Hematology. : abstr. 3662, 8 Dec 2008. Available from: URL: http://www.hematology.org. (English).
8. Nereus Pharmaceuticals Inc. Nereus Pharmaceuticals Raises $45 Million in Series D-2 Financing. Media Release. : 9 Aug 2007. Available from: URL: http://www.nereuspharm.com. (English).
9. Roccaro A, Leleu X, et al. The combination of bortezomib and NPI-0052 exerts anti-tumor activity in Waldenstrom macroglobulinemia. Blood. 110: 454, No. 11, Part 1, 16 Nov 2007. (English).
10. Baritaki S, Yeung K, et al. Inductin of Raf-1 kinase inhibitory protein by the proteasome inhibitor NPI-0052 and reversal of B-NHL resistance to apoptosis. Blood. 110: 248, No. 11, Part 1, 16 Nov 2007. (English).
11. Price T, Millward M, et al. A two-arm phase 1 clinical trial with NPI-0052, a novel proteasome inhibitor. 21st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. : abstr. C33, 15 Nov 2009. Available from: URL: http://www.aacr.org/ home/scientists/meetings--workshops/molecular-targets-and-cancer- therapeutics.aspx. (English).
12. Kruzrock R, Hamlin P, et al. NPI-0052 (a 2nd generation proteasome inhibitor) phase 1 study in patients with lymphoma and solid tumors. 20th-EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. : 73-74 abstr. 234, 22 Oct 2008. Available from: URL: http://www.ecco-org.eu. (English).
13. Townsend A, Padrik P, et al. Phase I clinical trial of the 2nd generation proteasome inhbitor NPI-0052 in patients with advanced malignancies with a CLL RP2D cohort. 20th-EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. : 74 abstr. 236, 22 Oct 2008. Available from: URL: http://www.ecco-org.eu. (English).
14. Miller B, Bahjat R, et al. Development of a structurally and biologically novel, oral proteasome inhibitor. 95th Annual Meeting of the American Association for Cancer Research. 45: 472, Mar 2004. (English).
15. Singh AV, Lloyd GK, et al. Pharmacodynamic and efficacy studies of a novel proteasome inhibitor NPI-0052 in human plasmacytoma xenograft mouse model. 50th Annual Meeting and Exposition of the American Society of Hematology. : abstr. 3665, 8 Dec 2008. Available from: URL: http://www.hematology.org. (English).
16. Baritaki S, Chapman A, et al. The novel proteasome inhibitor NPI-0052 induces the expression of Raf-1 kinase inhibitor protein RKIP in B-NHL via inhibition of the transcription repressor Snail: roles of Snail and RKIP in sensitization to TRAIL apoptosis. 50th Annual Meeting and Exposition of the American Society of Hematology. : abstr. 2611, 7 Dec 2008. Available from: URL: http:// www.hematology.org. (English).
17. Nereus Pharmaceuticals Inc. Nereus Pharmaceuticals Reports Positive Preclinical Results of Anti-Cancer Drug Candidates Derived from Marine Microbes at AACR Annual Meeting. Media Release. : 29 Mar 2004. Available from: URL: http://www.nereuspharm.com. (English).
18. Chauhan D, Li G, et al. A novel orally available proteasome inhibitor NPI-0052 induces killing in multiple myeloma cells resistant to conventional and bortezomib therapies. Blood. 104: 661, No. 11, Part 1, 16 Nov 2004. (English).
19. Chauhan D, Singh A, et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood. 110: 744, No. 11, Part 1, 16 Nov 2007. (English).
20. Miller CP, Rudra S, et al. Caspase-8 and oxidant dependent hyper- acetylation of histone-H3 by the novel proteasome inhibitor NPl-0052. 100th Annual Meeting of the American Association for Cancer Research. : abstr. 5633, 22 Apr 2009. Available from: URL: http://www.aacr.org. (English).

Revision Date: November 19, 2009
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