Genta (company)

Last updated
Genta, Inc.
Industry Biotechnology
Headquarters Berkeley Heights, New Jersey
Products Genasense, Tesetaxel, Ganite,
Website www.genta.com

Genta Incorporated was a biopharmaceutical company started in La Jolla, California, which discovered and developed innovative drugs for the treatment of patients with cancer. Founded in 1989 by a highly skilled entrepreneur, [1] the company focused on a novel technology known as antisense, which targets gene products that are associated with the onset and progression of serious diseases. At that time, only Ionis Pharmaceuticals, Inc. (Nasdaq :  IONS) (formerly Isis Pharmaceuticals until December 2015) [2] was conducting significant research with this technology. Antisense is a short span of oligonucleotides – modified DNA structures ranging from about 12-24 bases that selectively bind to specific RNA. The intent is to block expression of an aberrant protein that contributes to the disease of interest. Genta in-licensed three different antisense molecules that blocked Bcl-2, a fibroblast growth factor (FGF), and the gene c-myb, respectively.

Contents

Overview

Products

Genasense (oblimersen sodium)

A potent Bcl-2 antisense molecule was discovered and patented by Dr. John Reed, one of the world's highly ranked scientists. [3] Working with Dr. Carlo Croce, Reed was a key figure in understanding the central role of apoptosis in cancer cell death. Reed and others showed that cell-death in multiple types of cancer cells was blocked by expression of Bcl-2 protein. As a corollary, they showed that inhibitors of Bcl-2 function – or reduced expression of Bcl-2 protein – greatly enhanced cancer-killing activity when combined with conventional anticancer therapy.

Through the mid 1990s, drug development of oligonucleotides was slowed by the enormous cost of synthesizing custom DNA molecules. Moreover, animal studies showed the drug had to be injected in order to be effective, whereas oral administration led to rapid breakdown.

In 1995, Genta developed a clinical protocol for the first in-human study with a Bcl-2 inhibitor. While experts were highly enthusiastic about the approach, there was concern that very low drug supplies (due to very high cost) would constrain observations of clinical benefit. Nonetheless, based on pre-clinical work showing chemotherapy sensitization of melanoma cells, [4] a small Phase 1 study restricted to 14 patients with advance malignant melanoma was initiated in 1997 that reported acceptable safety and evidence of clinical activity. [5]

By then, a publicly traded company with financial constraints, external investors assumed control of Genta and initiated reductions in activity and expenses. The company was eventually able to restore market confidence and secured sufficient financing to expand clinical trials using “Genasense”, the new name for its Bcl-2 inhibitor.

In clinical trials, the underlying scientific premise was that blocking Bcl-2 expression would enhance the cancer-killing effects of standard anticancer therapy. As a corollary, however, this concept implied that convincing evidence of activity would require a direct comparison with standard treatment. Between 2001 and 2004, Genta initiated and completed three, global, randomized studies in melanoma, myeloma, and chronic lymphocytic leukemia. Given exceptionally poor patient outcomes in melanoma, a randomized double-blind trial was initiated using a standard drug (dacarbazine) with or without Genasense. The initial size of this trial was expanded to enable a direct comparison of safety and efficacy, which involved 139 research sites in 9 countries. Results showed statistically significant benefits (p < 0.05) in progression-free survival (PFS), overall response rate, and complete response rate. Overall survival also increased (9.0 vs.7.8 mos.; p = 0.077) but did not achieve statistical significance. [6]

Genasense had already been granted “Fast Track” status by the U.S. Food and Drug Administration (FDA). External reviews by melanoma experts suggested these data could be sufficient for conditional regulatory approval by FDA, subject to conduct of a follow-on confirmatory study. External reviewers also noted: (1) no drug had ever shown a survival improvement in melanoma; (2) no drug had ever been required to show increased survival by any regulatory authority; (3) the melanoma drug most recently considered for approval by FDA in melanoma (temozolomide; Temodar; Schering Plough) had been reviewed on the basis of whether there was statistically significant improvement in progression-free survival, which had not been achieved.

Together, these considerations strongly suggested that the significant increase in PFS, together with increased response rates and the trend in overall survival, would be favorably considered. At a FDA Advisory Committee on May 3, 2004, the Genasense data were felt to be insufficient, and the drug was not approved. [7] A followup study by Genta, which was intended to show a survival benefit in a subset of patients with advanced melanoma, was unsuccessful.

Genasense faced a similar regulatory outcome in the review of its randomized trial of standard chemotherapy with or without Genasense in patients with chronic lymphocytic leukemia (CLL). In this trial, the primary endpoint was response rate – a primary approval endpoint for other CLL drugs, but more rigorously defined in this study as limited to complete plus nodular partial response (CR/nPR). [8] In a study of 241 patients, the CR/nPR rate was significantly increased to 17% in patients who received Genasense plus chemotherapy vs. 7% who received chemotherapy alone (p = 0.025). Patents who achieved CR/nPR on the Genasense arm also demonstrated statistically superior increases in both overall survival as well as progression-free survival compared with patients who achieved CR/nPR using chemotherapy alone. Despite achieving the primary endpoint, on September 6, 2006 at an FDA Advisory Committee meeting, the overall patient benefit was considered modest and insufficient for approval. [9]

Followup of the Genasense Development Program

Throughout the period from 2004-2015, progression-free survival (PFS) was widely accepted as a primary approval endpoint for patients with solid tumors. Temozolomide (Temodar) had been approved in brain cancer, and the drug continued to be widely used off-label in patients with melanoma. [10]

In 2016, a different Bcl-2 inhibitor (venetoclax: Venclexta) (Genentech/AbbVie) was approved by FDA after a single non-randomized trial of relapsed CLL patients with 17p deletion, and on the basis of overall response rate (i.e., all types, complete plus partial), with a safety profile similar to Genasense. [11]

Genta halted the development of Genasense in 2008. The company also elected not to pursue clinical development of antisense drugs targeting FGF or c-myb. Genasense was the first systemic antisense drug to undergo global regulatory review. Since then, more than 10 different antisense drugs have been approved for patients with a wide range of serious clinical illnesses.

Tesetaxel

Tesetaxel is a novel taxane that is being developed as cancer therapy. Unlike standard taxanes (paclitaxel Taxol; docetaxel (Taxotere) that require slow intravenous administration and are mainstays of cancer treatment, tesetaxel is taken by mouth. The drug also appeared to cause fewer side-effects than IV taxanes. Preclinically, tesetaxel demonstrated substantially higher activity against cancer cell lines that were resistant to paclitaxel and docetaxel, since acquired resistance to this drug class is not mediated by the multidrug-resistant p-glycoprotein.

Discovered by Daiichi Sankyo Pharmaceutical Company, Tokyo, Japan, tesetaxel was tested by Daiichi in early Phase 1 and Phase 2 studies. However, the drug was placed on “clinical hold” by the U.S Food and Drug Administration due to deaths of several patients with severe blood count depression, and Daiichi's efforts to remove the regulatory hold were unsuccessful.

On May 7, 2008, Genta entered into a licensing agreement for global rights to tesetaxel with Daiichi Sankyo. [12] [13] Shortly thereafter, Genta secured FDA's agreement to remove the clinical hold with a brief submission that ensured patient safety.

Between 2008-2012, Genta conducted an array of Phase 1 and Phase 2 studies, [14] [15] [16] [17] [18] [19] [20] and subsequently the company initiated two global Phase 3 trials of tesetaxel in combination with capecitabine in breast cancer and gastric cancer, respectively. With positive Phase 3 data, Genta projected potential FDA approval and commercial U.S. launch of tesetaxel for treatment of metastatic breast cancer in 2014. However, financial constraints forced termination of the Phase 3 programs in 2012.[ citation needed ]

Global rights to tesetaxel were acquired from the Genta estate in 2013. Clinical development of tesetaxel was resumed by Odanate Therapeutics (ODT; Nasdaq), which is conducting Phase 3 studies for its approval in breast cancer.[ citation needed ]

Gallium Products

With the emergence of platinum-based drugs as cancer treatment, the U.S. National Cancer Institute initiated a screening program for other metals as anticancer drugs in the 1970s. 67Ga was already being used in radiology scans to image potential areas of inflammation and some types of cancer, and gallium nitrate emerged as a potentially effective anticancer agent. [21] Early clinical studies unexpectedly showed that gallium nitrate markedly reduced serum calcium, [22] which when elevated is a potentially life-threatening complication in cancer patients.

With this discovery, a team at Memorial Sloan-Kettering in New York initiated a clinical development program that showed the drug was highly effective. [23] Follow-on Phase 3 randomized trials showed the drug was superior to other agents used at that time, including injectable calcitonin [24] and intravenous etidronate. [25] Concurrent studies also suggested clinical activity in patients with severe hypercalcemia due to parathyroid carcinoma [26] as well as patients with bone diseases, including Paget's disease, [27] [28] multiple myeloma, [29] [30] and bone metastases. [31] In 2003, the drug was approved as Ganite® (gallium nitrate solution) for the treatment of hypercalcemia resistant to hydration, and the drug was marketed by Fujisawa Inc.

Work at the Hospital for Special Surgery in New York and elsewhere suggested that gallium reduced bone resorption and might also stimulate bone formation. [32] [33] [34] Collectively, this information suggested the drug might be useful for treatment of diseases associated with accelerated bone loss, included bone metastases, Paget's disease, and osteoporosis. Genta Inc. acquired global rights to the marketed drug in 2001, and filed an IND and NDA (both approved by FDA) in 2002 and 2003, respectively. However, the regulatory failure of Genasense in melanoma caused termination of the marketing program for Ganite. Nonetheless, research with gallium-containing compounds was pursued in women with breast cancer and metastatic bone disease.

To improve patient convenience, Genta developed and patented an oral formulation of gallium known as G4544, [35] and the company filed an IND and conducted a preliminary clinical study of G544 that showed superior oral absorption. [36]

Based on discovery work at the University of Washington, [37] in 2010 Genta tested an infusion of Ganite in the first patient with cystic fibrosis , [38] demonstrating safety and potential therapeutic concentrations of gallium for reducing Pseudomonas aeruginosa bacterial infections. Genta also supported the clinical follow-on study at the University of Washington with regulatory cross-reference of both the Ganite IND and drug supply.

Despite promising results, all work on therapeutic gallium compounds by Genta ceased in 2012 due to financial conditions. The cystic fibrosis work has continued to be supported by the Cystic Fibrosis Foundation. Gallium nitrate is currently being administered to patients via inhalation.

Other Products

The Genasense setbacks prompted termination of two other Genta projects, both in preclinical stages. Galaterone, a drug in-licensed from the University of Maryland, was a small molecule intended for treatment of prostate cancer. As a compound acting as both an androgen receptor antagonist and an inhibitor of CYP17, the drug appeared to have substantial promise. Upon Genta's termination of its license, Gelaterone was re-licensed to Tokai Pharmaeuticals, Inc. In order to expand its nucleotide franchise, Genta had purchased Salus Therapeutics and acquired a portfolio of small interfering ribonucleic acid technologies (siRNA), which also could not be developed due to financial constraints.

Company Operations

With funding constraints and serial layoffs in the mid-to-late 1990s, Genta had been reduced to six employees. In 1997, the La Jolla facility was closed and the company was moved to Lexington, MA. A new CEO was recruited in late 1999 who opened a temporary office in New York. New Jersey was then a home for global pharmaceutical companies and experienced employees. Genta moved from Lexington, MA into temporary space in Short Hills, NJ, and then into permanent space in Berkeley Heights, NJ, where it remained for the next 12 years.

Financial History

New management initiated a vigorous business development program to secure co-development funding for the costly Genasense programs. In April 2002, having initiated Phase 3 trials and solicited interest from a number of multinational companies, Genta signed a global development and licensing deal with Aventis Incorporated. [39] At that time, the nominal $480 million deal was the second largest ever concluded for a single-product oncology compound (just behind Erbitux®; Imclone Systems to Bristol Myers Squibb). [40] [41] However, the Genta deal also included funding for U.S. clinical development expenses estimated at an additional $400 million, U.S. co-marketing rights with 50% coverage of Genta's marketing expenses, 100% coverage of all ex-U.S. clinical development expenses, escalating double-digit royalties on U.S. and global sales, and a $75 million investment via a convertible loan.

Despite disappointing survival results from the Phase 3 melanoma trial, both companies favored submission of a New Drug Application, [42] [43] which was not approved by FDA in 2004. Aventis and Genta terminated their agreement in May 2005 with provisions for continued funding of the Phase 3 CLL program. Over the 3-year duration, Aventis had contributed $270 million to Genta.

Following termination, fund-raising to support ongoing programs was considerably constrained, which prompted serial workforce reductions and cost-saving initiatives. Despite positive Phase 3 data, in 2006 the New Drug Application in CLL was not approved by FDA. Having previously secured FDA's Special Protocol Assessment requiring a post-approval confirmatory study, FDA's decision not to consider the initial study as supportive was appealed by Genta and it was reversed by FDA in 2009. [44] FDA reaffirmed the requirement for a confirmatory trial, which Genta had not contested. However, the extended appeal and continued funding challenges precluded further study of Genta's Bcl-2 inhibitor in CLL.

By 2008, company funds were insufficient to proceed, and Genta issued a series of convertible notes to supportive investors, which provided credence to its subsequent development programs. Over the subsequent four years, however, Genta stock came under intensive pressure as it became a “penny stock” that required several “reverse stock splits”. The company stock was also temporarily delisted from the Nasdaq stock exchange.

By mid June 2012, the company believed it had secured additional financing to both remain on Nasdaq and to continue its Phase 3 studies with tesetaxel, which ultimately failed to close. Lacking financial alternatives, Genta filed for Chapter 7 bankruptcy in August 2012 [45] and ceased operations.

Related Research Articles

<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. It was the first apoptosis regulator identified in any organism.

<span class="mw-page-title-main">Small-cell carcinoma</span> Type of malignant cancer

Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma has a shorter doubling time, higher growth fraction, and earlier development of metastases.

<span class="mw-page-title-main">Docetaxel</span> Chemotherapy medication

Docetaxel, sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cell lung cancer. It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Lapatinib</span> Cancer medication

Lapatinib (INN), used in the form of lapatinib ditosylate (USAN) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Oblimersen is an antisense oligodeoxyribonucleotide being studied as a possible treatment for several types of cancer, including chronic lymphocytic leukemia, B-cell lymphoma, and breast cancer. It may kill cancer cells by blocking the production of Bcl-2—a protein that makes cancer cells live longer—and by making them more sensitive to chemotherapy.

<span class="mw-page-title-main">Eribulin</span> Pharmaceutical drug

Eribulin, sold under the brand name Halaven, is an anticancer medication used to treat breast cancer and liposarcoma.

<span class="mw-page-title-main">Gallium nitrate</span> Chemical compound

Gallium nitrate (brand name Ganite) is the gallium salt of nitric acid with the chemical formula Ga(NO3)3. It is a drug used to treat symptomatic hypercalcemia secondary to cancer. It works by preventing the breakdown of bone through the inhibition of osteoclast activity, thus lowering the amount of free calcium in the blood. Gallium nitrate is also used to synthesize other gallium compounds.

A CDK inhibitor is any chemical that inhibits the function of CDKs. They are used to treat cancers by preventing overproliferation of cancer cells. The US FDA approved the first drug of this type, palbociclib (Ibrance), a CDK4/6 inhibitor, in February 2015, for use in postmenopausal women with breast cancer that is estrogen receptor positive and HER2 negative. Several compounds are in clinical trials.

Glembatumumab vedotin is an antibody-drug conjugate (ADC) that targets cancer cells expressing transmembrane glycoprotein NMB (GPNMB).

<span class="mw-page-title-main">Cabazitaxel</span> Chemical compound

Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.

<span class="mw-page-title-main">Zoptarelin doxorubicin</span> Chemical compound

Zoptarelin doxorubicin consists of doxorubicin linked to a small peptide agonist to the luteinizing hormone-releasing hormone (LHRH) receptor. It has been developed as a potential treatment for a number of human cancers. The LHRH receptor is aberrantly present on the cell surface of approximately 80% of endometrial and ovarian cancers, 86% of prostate cancers and about 50% of breast cancers. Whereas in normal tissues, expression of this receptor is mainly confined to the pituitary gland, reproductive organs and hematopoietic stem cells. To a lesser extent the LHRH receptor is also found on the surface of bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas.

<span class="mw-page-title-main">Trastuzumab emtansine</span> Pharmaceutical drug

Trastuzumab emtansine, sold under the brand name Kadcyla, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the cytotoxic agent DM1. Trastuzumab alone stops growth of cancer cells by binding to the HER2 receptor, whereas trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death. Trastuzumab binding to HER2 prevents homodimerization or heterodimerization (HER2/HER3) of the receptor, ultimately inhibiting the activation of MAPK and PI3K/AKT cellular signalling pathways. Because the monoclonal antibody targets HER2, and HER2 is only over-expressed in cancer cells, the conjugate delivers the cytotoxic agent DM1 specifically to tumor cells. The conjugate is abbreviated T-DM1.

<span class="mw-page-title-main">Nivolumab</span> Cancer drug

Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer. It is used by slow injection into a vein.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is given by slow injection into a vein.

<span class="mw-page-title-main">Binimetinib</span> Chemical compound

Binimetinib, sold under the brand name Mektovi, is an anti-cancer medication used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. It was developed by Array Biopharma.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Custirsen</span> Chemical compound

Custirsen, with aliases including custirsen sodium, OGX-011, and CC-8490, is an investigational drug that is under clinical testing for the treatment of cancer. It is an antisense oligonucleotide (ASO) targeting clusterin expression. In metastatic prostate cancer, custirsen showed no benefit in improving overall survival.

References

  1. ↑ "GENTA $ 8.4 MIL. FOLLOW-UP VENTURE FUNDING EXCEEDS TARGET: FIRM PLANS IND THIS AUTUMN FOR SYSTEMIC ANTISENSE PRODUCT FOR CHRONIC MYELOGENOUS LEUKEMIA". Medtech Insight. August 19, 1991. Retrieved 7 December 2019.
  2. ↑ Fikes, Bradley (18 December 2015). "From Isis Pharma to Ionis". The San Diego Union-Tribune. Retrieved 22 December 2015.
  3. ↑ "SCIENTIST AT WORK: John Reed; Running Hot in Pursuit of Cancer Treatment". The New York Times. December 12, 2000. Retrieved 24 November 2019.
  4. ↑ "bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice". Janssen. February 1, 1998. Retrieved 24 November 2019.
  5. ↑ "Chemosensitisation of malignant melanoma by BCL2 antisense therapy". The Lancet. November 18, 2000. Retrieved 24 November 2019.
  6. ↑ Bedikian, Agop Y.; Millward, Michael; Pehamberger, Hubert; Conry, Robert; Gore, Martin; Trefzer, Uwe; Pavlick, Anna C.; Deconti, Ronald; Hersh, Evan M.; Hersey, Peter; Kirkwood, John M.; Haluska, Frank G. (October 10, 2006). "Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group". Journal of Clinical Oncology. 24 (29): 4738–4745. doi: 10.1200/JCO.2006.06.0483 . PMID   16966688.
  7. ↑ "DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ONCOLOGIC DRUG ADVISORY COMMITTEE". Archived from the original on 4 April 2017. Retrieved 24 November 2019.
  8. ↑ O'Brien, Susan; Moore, Joseph O.; Boyd, Thomas E.; Larratt, Loree M.; Skotnicki, Aleksander; Koziner, Benjamin; Chanan-Khan, Asher A.; Seymour, John F.; Bociek, R. Gregory; Pavletic, Steve; Rai, Kanti R. (March 20, 2007). "Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia". Journal of Clinical Oncology. 25 (9): 1114–1120. doi:10.1200/JCO.2006.07.1191. PMID   17296974.
  9. ↑ "DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ONCOLOGIC DRUGS ADVISORY COMMITTEE DAY ONE - MORNING SESSION" (PDF). Archived from the original (PDF) on 4 April 2017. Retrieved 24 November 2019.
  10. ↑ Li, R. H.; Hou, X. Y.; Yang, C. S.; Liu, W. L.; Tang, J. Q.; Liu, Y. Q.; Jiang, G. (2015). "Temozolomide for Treating Malignant Melanoma". Journal of the College of Physicians and Surgeons Pakistan. Vol. 25, no. 9. pp. 680–8. PMID   26374366.
  11. ↑ "FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality". U.S Food and Drug Administration. April 11, 2016. Retrieved 24 November 2019.
  12. ↑ "Genta Announces Licensing Agreement for Worldwide Development and Commercialization of a Leading Oral Taxane, Tesetaxel". March 7, 2008. Retrieved 26 November 2019.
  13. ↑ "Genta Licenses Daiichi Sankyo Oncology Drug on Clinical Hold" . Retrieved 26 November 2019.
  14. ↑ "Phase I/II Study of a 3 Weekly Oral Taxane (DJ-927) in Patients with Recurrent, Advanced Non-small Cell Lung Cancer" . Retrieved 26 November 2019.
  15. ↑ "Tesetaxel as First-line Therapy for Metastatic Breast Cancer" . Retrieved 26 November 2019.
  16. ↑ "Tesetaxel in Chemotherapy-naive Patients With Progressive, Castration-resistant Prostate Cancer" . Retrieved 26 November 2019.
  17. ↑ "Tesetaxel in Chemotherapy-naive Patients With Progressive, Castration-resistant Prostate Cancer" . Retrieved 26 November 2019.
  18. ↑ "Tesetaxel in Chemotherapy-naive Patients With Progressive, Castration-resistant Prostate Cancer" . Retrieved 26 November 2019.
  19. ↑ "Tesetaxel in Chemotherapy-naive Patients With Progressive, Castration-resistant Prostate Cancer" . Retrieved 26 November 2019.
  20. ↑ "Tesetaxel in Chemotherapy-naive Patients With Progressive, Castration-resistant Prostate Cancer" . Retrieved 26 November 2019.
  21. ↑ Hall, S. W.; Yeung, K.; Benjamin, R. S.; Stewart, D.; Valdivieso, M.; Bedikian, A. Y.; Loo, T. L. (1979). "Kinetics of gallium nitrate, a new anticancer agent". Clinical Pharmacology and Therapeutics. 25 (1): 82–7. doi:10.1002/cpt197925182. PMID   758246. S2CID   24256012.
  22. ↑ "Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia" . Retrieved 5 December 2019.
  23. ↑ "Gallium Nitrate for Acute Treatment of Cancer-related Hypercalcemia: Clinicopharmacological and Dose Response Analysis" . Retrieved 5 December 2019.
  24. ↑ Warrell Jr, R. P.; Israel, R.; Frisone, M.; Snyder, T.; Gaynor, J. J.; Bockman, R. S. (1988). "Gallium nitrate for acute treatment of cancer-related hypercalcemia. A randomized, double-blind comparison to calcitonin". Annals of Internal Medicine. 108 (5): 669–74. doi:10.7326/0003-4819-108-5-669. PMID   3282463.
  25. ↑ "A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia". PMID   1906532.
  26. ↑ "Gallium nitrate for treatment of refractory hypercalcemia from parathyroid carcinoma". PMID   2821862.
  27. ↑ "Use of gallium to treat Paget's disease of bone: a pilot study" . Retrieved 5 December 2019.
  28. ↑ "A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone" . Retrieved 5 December 2019.
  29. ↑ Warrell, R. P.; Lovett, D.; Dilmanian, F. A.; Schneider, R.; Heelan, R. T. (1993). "Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study". Journal of Clinical Oncology. 11 (12): 2443–2450. doi:10.1200/JCO.1993.11.12.2443. PMID   8246033.
  30. ↑ "Gallium nitrate in multiple myeloma: prolonged survival in a cohort of patients with advanced-stage disease". PMID   12776256.
  31. ↑ "FDA Approves Ganite for Hypercalcemia" . Retrieved 5 December 2019.
  32. ↑ Bockman, R. S.; Boskey, A. L.; Blumenthal, N. C.; Alcock, N. W.; Warrell, R. P. (1986). "Gallium increases bone calcium and crystallite perfection of hydroxyapatite". Calcified Tissue International. 39 (6): 376–381. doi:10.1007/BF02555174. PMID   3026592. S2CID   21977045.
  33. ↑ "Gallium inhibits bone resorption by a direct effect on osteoclasts". PMID   2278540.
  34. ↑ "The effects of gallium nitrate on bone resorption". PMID   12776254.
  35. ↑ "Genta Announces Issuance of Two Key U.S. Patents for its Gallium Products Franchise" . Retrieved 5 December 2019.
  36. ↑ Novick, S. C.; Julian, T. N.; Majuru, S.; Mangelus, M.; Brown, B. D.; Mehta, B.; Warrell, R. P. (2008). "Initial phase I clinical and pharmacokinetic assessment of G4544, an oral gallium-containing compound". Journal of Clinical Oncology. 26 (15_suppl): 8592. doi:10.1200/jco.2008.26.15_suppl.8592.
  37. ↑ Goss, Christopher H.; Kaneko, Yukihiro; Khuu, Lisa; Anderson, Gail D.; Ravishankar, Sumedha; Aitken, Moira L.; Lechtzin, Noah; Zhou, Guolin; Czyz, Daniel M.; McLean, Kathryn; Olakanmi, Oyebode; Shuman, Howard A.; Teresi, Mary; Wilhelm, Ellen; Caldwell, Ellen; Salipante, Stephen J.; Hornick, Douglas B.; Siehnel, Richard J.; Becker, Lev; Britigan, Bradley E.; Singh, Pradeep K. (2018). "Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections". Science Translational Medicine. Vol. 10, no. 460. doi:10.1126/scitranslmed.aat7520 . Retrieved 5 December 2019.
  38. ↑ "Abstract 1678: Systemic gallium nitrate therapy results in sustained sputum concentrations that may be therapeutic for biofilm-associated pulmonary bacterial infections" . Retrieved 5 December 2019.
  39. ↑ "Genta, Aventis in $480 million pact" . Retrieved 7 December 2019.
  40. ↑ "Genta's Tangled Path" . Retrieved 7 December 2019.
  41. ↑ "Aventis and Partner Genta Say Cancer Drug Is on Track" . Retrieved 7 December 2019.
  42. ↑ "Genta, Aventis see hope for drug" . Retrieved 7 December 2019.
  43. ↑ "Genta and Aventis Terminate Genasense® Agreements" . Retrieved 7 December 2019.
  44. ↑ "FDA Appeal Decision Indicates that Genasense® Approval in Chronic Lymphocytic Leukemia Will Require Additional Confirmatory Trial" . Retrieved 7 December 2019.
  45. ↑ "8-K 1 genta_8k-080212.htm FORM 8K" . Retrieved 7 December 2019.

40°39′50″N74°24′53″W / 40.6638°N 74.4148°W / 40.6638; -74.4148

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.