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Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma
CAL 101, IDELALISIB
SEPT 2013
Gilead Submits New Drug Application to U.S. FDA for Idelalisib for the Treatment of Indolent Non-Hodgkin’s Lymphoma
FOSTER CITY, Calif.–(BUSINESS WIRE)–Sep. 11, 2013– Gilead Sciences, Inc. today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of idelalisib, an investigational, targeted, oral inhibitor of PI3K delta, for the treatment of indolent non-Hodgkin’s lymphoma (iNHL). The data submitted in this NDA support the use of idelalisib for patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy.
read all at
Idelalisib ….US FDA Accepts NDA for Gilead’s Idelalisib for the Treatment of Refractory Indolent Non-Hodgkin’s Lymphoma
JANUARY 14, 2014 8:35 AM / LEAVE A COMMENT
An antineoplastic agent and p110delta inhibitor
(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
Icos (Originator)
- CAL-101
- GS-1101
- Idelalisib
- UNII-YG57I8T5M0
M.Wt: 415.43
Formula: C22H18FN7O
CAS No.: 870281-82-6
CAL-101 Solubility: DMSO ≥80mg/mL Water <1.2mg/mL Ethanol ≥33mg/mL
5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone
idelalisib
Idelalisib (codenamed GS-1101 or CAL-101) is a drug under investigation for the treatment of chronic lymphocytic leukaemia. It is in Phase III clinical trials testing drug combinations with rituximab and/or bendamustine as of 2013. The substance acts as aphosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase.[1][2]
GDC-0032 is a potent, next-generation beta isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with IC 50 of 0.29 nM/0.12 nM/0.97nM,> 10 fold over Selective PI3K [beta].
GS-1101 is a novel, orally available small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) develop by Gilead and is waiting for registration in U.S. for the treatment of patients with indolent non-Hodgkin’s lymphoma that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy and for the treatment of chronic lymphocytic leukemia. The compound is also in phase III clinical evaluation for the treatment of elderly patients with previously untreated small lymphocytic lymphoma (SLL) and acute myeloid leukemia. Clinical trials had been under way for the treatment of inflammation and allergic rhinitis; however, no recent development has been reported. Preclinical studies have shown that GS-1101 has desirable pharmaceutical properties. The compound was originally developed by Calistoga Pharmaceuticals, acquired by Gilead on April 1, 2011.
clinical trials, click link
http://clinicaltrials.gov/search/intervention=CAL-101%20OR%20GS-1101%20OR%20Idelalisib
FOSTER CITY, Calif.–(BUSINESS WIRE)–Jan. 13, 2014– Gilead Sciences, Inc. (Nasdaq: GILD) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the company’s New Drug Application (NDA) for idelalisib, a targeted, oral inhibitor of PI3K delta, for the treatment of refractory indolent non-Hodgkin’s lymphoma (iNHL). FDA has granted a standard review for the iNHL NDA and has set a target review date under the Prescription Drug User Fee Act (PDUFA) of September 11, 2014.
The NDA for iNHL, submitted on September 11, 2013, was supported by a single arm Phase 2 study (Study 101-09) evaluating idelalisib in patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy. Following Gilead’s NDA submission for iNHL, FDA granted idelalisib a Breakthrough Therapy designation for relapsed chronic lymphocytic leukemia (CLL). The FDA grants Breakthrough Therapy designation to drug candidates that may offer major advances in treatment over existing options. Gilead submitted an NDA for idelalisib for the treatment of CLL on December 6, 2013.
About Idelalisib
Idelalisib is an investigational, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta. PI3K delta signaling is critical for the activation, proliferation, survival and trafficking of B lymphocytes and is hyperactive in many B-cell malignancies. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.
Gilead’s clinical development program for idelalisib in iNHL includes Study 101-09 in highly refractory patients and two Phase 3 studies of idelalisib in previously treated patients. The development program in CLL includes three Phase 3 studies of idelalisib in previously treated patients. Combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, also is being evaluated in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid malignancies.
Additional information about clinical studies of idelalisib and Gilead’s other investigational cancer agents can be found at http://www.clinicaltrials.gov. Idelalisib and GS-9973 are investigational products and their safety and efficacy have not been established.
About Indolent Non-Hodgkin’s Lymphoma
Indolent non-Hodgkin’s lymphoma refers to a group of largely incurable slow-growing lymphomas that run a relapsing course after therapy and can lead ultimately to life-threatening complications such as serious infections and marrow failure. Most iNHL patients are diagnosed at an advanced stage of disease, and median survival from time of initial diagnosis for patients with the most common form of iNHL, follicular lymphoma, is 8 to 10 years. The outlook for refractory iNHL patients is significantly poorer.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.
The delta form of PI3K is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies, inflammation, autoimmune diseases and allergies. By specifically inhibiting only PI3K delta, a therapeutic effect is exerted without inhibiting PI3K signalling that is critical to the normal function of healthy cells. Extensive studies have shown that inhibition of other PI3K forms can cause significant toxicities, particularly with respect to glucose metabolism, which is essential for normal cell activity.
In 2011, orphan drug designation was assigned to GS-1101 in the U.S. for the treatment of CLL. In 2013, several orphan drug designations were assigned to the compound in the E.U. and U.S.: for the treatment of follicular lymphoma, for the treatment of mucosa-associated lymphoid tissue lymphoma (MALT), for the treatment of nodal marginal zone lymphoma, for the treatment of splenic marginal zone lymphoma, and for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma. Orphan drug designation was also assigned in the U.S. for the treatment of lymphoplasmacytic lymphoma with or without Walenstom’s macroglobulinemia and, in the E.U., for the treatment of Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).
Later in 2013, some of these orphan drug designations were withdrawn in the E.U.; for the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma, for the treatment of extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), for the treatment of of nodal marginal-zone lymphoma and for the treatment of splenic marginal-zone lymphoma. In 2013, the FDA granted a breakthrough therapy designation for the treatment of chronic lymphocytic leukemia.
- H. Spreitzer (13 May 2013). “Neue Wirkstoffe – Ibrutinib und Idelalisib”. Österreichische Apothekerzeitung (in German) (10/2013): 34.
- Wu, M.; Akinleye, A.; Zhu, X. (2013). “Novel agents for chronic lymphocytic leukemia”.Journal of Hematology & Oncology 6: 36. doi:10.1186/1756-8722-6-36.PMC 3659027. PMID 23680477.
CAL-101 is an Oral Delta Isoform-Selective PI3 Kinase Inhibitor.
| US8207153 | 6-27-2012 | QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA |
| US2012015964 | 1-20-2012 | QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA |
| US2011306622 | 12-16-2011 | METHODS OF TREATING HEMATOLOGICAL DISORDERS WITH QUINAZOLINONE COMPOUNDS IN SELECTED SUBJECTS |
| US7932260 | 4-27-2011 | Quinazolinones as Inhibitors of Human Phosphatidylinositol 3-Kinase Delta |
| US2011044942 | 2-25-2011 | METHODS OF TREATMENT FOR SOLID TUMORS |
| US2010256167 | 10-8-2010 | QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA |
| US2010202963 | 8-13-2010 | THERAPIES FOR HEMATOLOGIC MALIGNANCIES |
| WO2005113556A1 * | 12 May 2005 | 1 Dec 2005 | Icos Corp | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| WO2005117889A1 * | 12 Nov 2004 | 15 Dec 2005 | Didier Bouscary | Methods for treating and/or preventing aberrant proliferation of hematopoietic |
| WO2005120511A1 * | 4 Jun 2005 | 22 Dec 2005 | Joel S Hayflick | Methods for treating mast cell disorders |
| WO2006089106A2 * | 16 Feb 2006 | 24 Aug 2006 | Icos Corp | Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation |
| US20060106038 * | 25 May 2005 | 18 May 2006 | Icos Corporation | Methods for treating and/or preventing aberrant proliferation of hematopoietic cells |
The synthesis of a compound in accordance with formula I is first exemplified using steps A-E below, which provide a synthetic procedure for compound 107, the structure of which is shown below.
(107) is idelalisib
……………….
Synthesis of 2-fluoro-6-nitro-N-phenyl-benzamide (108)
Step A: A solution of 2-fluoro-6- nitrobenzoic acid (100 g, 0.54 mol) and dimethylformamide (5 mL) in dichloromethane (600 mL) was treated dropwise with oxalyl chloride (2 M in dichloromethane, 410 mL, 0.8 mol, 1.5 eq) over 30 min. After stirring 2 h at room temperature, the reaction was concentrated to an orange syrup with some solids present. The syrup was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline (49 mL, 0.54 mol, 1 eq) and sodium bicarbonate (90 g, 1.08 mol, 2 eq) in a mixture of dioxane (250 mL) and water (250 mL) at 6 0C. The temperature reached 27°C at the end of the addition. After 30 min, the reaction mixture was treated with water (1.2 L). The precipitate was collected by vacuum filtration, washed with water (300 mL) , air dried in the funnel, and dried in vacuo at 50°C for 24 h to afford an off-white solid product (139 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, IH), 8.12 (d, J = 7.7 Hz, IH), 7.91-7.77 (m, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.15 > (t, J = 7.4 Hz, IH), ESI-MS m/z 261 (MH+). The reaction described above and compound 108 are shown below.
………………………..
Synthesis of(S) – [1- (2-fluoro-6-nitro-benzoyl) -phenyl-aminocarbonyl] – propyl-carbamic acid tert-butyl ester (109)
Step B: A suspension of compound 108 (0.5 mol) and dimethylformamide (5 mL) in thionyl chloride (256 mL, 2.5 mol, 5 eq) was stirred at 85°C for 5 hours. The reaction mixture was concentrated in vacuo to a brown syrup. The syrup was dissolved in dichloromethane (200 mL) and was slowly added to a solution of N-BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and triethylamine (77 mL, 0.55 mol, 1.1 eq) in dichloromethane (600 mL) at 10 0C. After stirring at room temperature for 3 h, salts were removed by filtration, and the solution was washed with 100 mL of water, saturated sodium bicarbonate, water, 5% citric acid, and saturated sodium chloride. The organic phase was dried with magnesium sulfate and concentrated to a red syrup. The syrup was dissolved in dichloromethane (450 mL) and purified by flash chromatography on a silica gel plug (15 x 22 cm, 4 L dry silica) eluted with hexanes/ethyl acetate (10%, 8 L; 15%, 8 L; 20%, 8 L; 25%, 4 L) to yield the compound 109 as an off-white solid (147 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J = 8.0 Hz, IH), 7.84 (t, J = 8.6 Hz, IH), 7.78- 7.67 (m, IH), 7.65-7.49 (m, 3H), 7.40-7.28 ( m, 2H), 7.19 (d, J = 7.5 Hz, IH), 4.05 (broad s, IH), 1.75- 1.30 (m, 2H), 1.34 (s, 9H), 0.93 (broad s, 3H). ESI- MS m/z 446.3 (MH+) . The reaction described above and compound 109 are shown below.
Synthesis of(S) – [1- (5-fluoro-4-oxo-3-phenyl-3 , 4-dihydro-quinazolin-2- yl) -propyl] -carbamic acid tert-butyl ester (110)
Step C: A solution of compound 109 (125 mmol, 1 eq) in acetic acid (500 mL) was treated with zinc dust (48.4 g, 740 mmol, 6 eq) added in 3 portions, and the reaction mixture was allowed to cool to below 35°C between additions. After stirring for 2 h at ambient temperature, solids were filtered off by vacuum filtration and washed with acetic acid (50 mL) . The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL) , washed with water (300 mL) , and the water layer was extracted with EtOAc (300 mL) . The combined organic layers were washed with water (200 mL) , sat’d sodium bicarbonate (2 x 200 mL) , sat’d NaCl (100 mL) , dried with MgSO4, and concentrated to a syrup. The syrup was dissolved in toluene (200 mL) and purified by flash chromatography on a silica gel plug (13 x 15 cm, 2 L dry silica) eluted with hexanes/ethyl acetate (10%, 4 L; 15%, 4 L; 17.5%, 8 L; 25%, 4 L) to yield compound 110 as an off-white foamy solid (33.6 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (td, J = 8.2, 5.7 Hz, IH), 7.64-7.48 (m, 5H), 7.39 (broad d, J = 7.6 Hz, IH), 7.30 (dd, J = 8.3 Hz, IH), 7.23 (d, J = 7.6 Hz, IH), 4.02-3.90 (m, IH), 1.76-1.66 (m, IH), 1.62-1.46 (m, IH), 1.33 (s, 9H), 0.63 (t, J= 7.3 Hz, 3H). ESI-MS m/z 398.3 (MH+). The reaction described above and compound 110 are shown below.
…………..
Syn of (S) -2- (1-amino-propyl) -5-fluoro-3-phenyl-3H-quinazolin-4- one (111)
Step D: A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL) . The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greated than 10) . The aqueous layer was extracted with additional dichloromethane (100 raL) , and the combined organic layers were washed with water (50 mli) and brine (50 mL) . After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%) . 1H NMR (300 MHz,
CDCl3) δ 7.73-7.65 (m, IH), 7.62-7.49 (m, 4H), 7.32- 7.22 (m, 2H), 7.13-7.06 (m, IH), 3.42 (dd, J= 7.5, 5.2 Hz, IH), 1.87-1.70 (m, IH), 1.58-1.43 (m, IH), 0.80 (t, J = 7.4 Hz, 3H) . ESI-MS m/z 298.2 (MH+) . The reaction described above and compound 111 are shown below.
………………
syn of (S) -5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -propyl] – 3H-quinazolin-4-one (107)
Step E: A suspension of compound 111(65.6 mmol, 1 eq) , 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq) , and DIEA (24.3 mL, 140 mmol, 2 eq) in tert- butanol (40 mL) was stirred for 24 h at 800C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the obtained solid crude product was dissolved in MeOH (600 mL) , concentrated onto silica gel (300 mL dry) , and purified by flash chromatography (7.5 x 36 cm, eluted with 10 L of 4% MeOH/CH2Cl2) to yield a solid product. The solid product was then dissolved in EtOH (250 mL) and concentrated in vacuo to compound 107 idelalisib as a light yellow solid (7.2 g, 50%).
1H NMR (300 MHz, 80 0C, DMSO-d5) δ 12.66 (broad s, IH), 8.11 (s, IH), 8.02 (broad s, IH), 7.81-7.73 (m, IH),7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, IH), 2.02-1.73 (m, 2H), 0.79 (t, J= 7.3 Hz, 3H).
ESI-MS m/z 416.2 (MH+).
C, H, N elemental analysis (C22Hi8N7OF-EtOH- 0.4 H2O).
Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6 x 250 mm Chiralpak ODH column, 20 °C, 85:15 hexanes : EtOH, 1 rnL/min, sample loaded at a concentration of 1 mg/mL in EtOH) . The reaction described above and compound 107 idelalisib are shown below.
| WO2001030768A1 * | 26 Oct 2000 | 3 May 2001 | Gustave Bergnes | Methods and compositions utilizing quinazolinones |
| WO2001081346A2 * | 24 Apr 2001 | 1 Nov 2001 | Icos Corp | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
| WO2003035075A1 * | 27 Aug 2002 | 1 May 2003 | Icos Corp | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
| WO2005016348A1 * | 13 Aug 2004 | 24 Feb 2005 | Jason Douangpanya | Method of inhibiting immune responses stimulated by an endogenous factor |
| WO2005016349A1 * | 13 Aug 2004 | 24 Feb 2005 | Thomas G Diacovo | Methods of inhibiting leukocyte accumulation |
| WO2005067901A2 * | 7 Jan 2005 | 28 Jul 2005 | Carrie A Northcott | Methods for treating and preventing hypertension and hypertension-related disorders |
European Commission Approves Stribild, a New Single Tablet Regimen for the Treatment of HIV-1 Infection
May. 28, 2013– Gilead Sciences, Inc. today announced that the European Commission has granted marketing authorization for Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg),
a single tablet regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild.
This approval allows for the marketing of Stribild in all 27 countries of the European Union.
Gilead Submits NDA to FDA for Sofosbuvir for the Treatment of Hepatitis C
Sofosbuvir
Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
9 APRIL 2013
Gilead Sciences today announced that the company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of sofosbuvir, a once-daily oral nucleotide analogue for the treatment of chronic hepatitis C virus (HCV) infection. The data submitted in this NDA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.
Chronic HCV infection affects up to four million Americans, particularly individuals born between 1946 and 1964. The disease is the leading cause of liver cancer and liver transplantation in the United States. Treatment for HCV currently includes 24-48 weeks of therapy with peg-IFN, which has to be injected and is associated with significant side effects, leaving some patients unable to complete therapy. If approved, sofosbuvir would shorten HCV therapy to 12 to 16 weeks, and depending on the genotype, would either eliminate or reduce the duration of peg-IFN injections.
“Current therapies are not suitable for large numbers of patients with HCV infection, and are challenging to take and tolerate,” said John C. Martin, PhD, Chairman and Chief Executive Officer of Gilead Sciences. “Sofosbuvir’s antiviral potency, safety profile and once-daily administration have the potential to improve cure rates by simplifying and shortening therapy for patients with this disease.”
The sofosbuvir NDA is supported primarily by data from four phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, in which 12 or 16 weeks of sofosbuvir-based therapy was found to be superior or non-inferior to currently available treatment options or historical controls, based on the proportion of patients who had a sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV.
Gilead plans to file for regulatory approval of sofosbuvir in other geographies, including the European Union, in the second quarter of 2013. The European Medicines Agency (EMA) has accepted Gilead’s request for accelerated assessment for sofosbuvir, a designation that is granted to new medicines of major public health interest. Accelerated assessment could shorten the EMA’s review time of sofosbuvir by two months. Granting of accelerated assessment does not guarantee a positive opinion from the CHMP or approval by the European Commission.
Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.[2]
Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.[3]
Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.
Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[6]
- Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
- “PSI-7977″. Gilead Sciences.
- Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347. doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
- Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
- Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
- http://www.gilead.com/pr_1757156
- AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
- Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
- CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
Phase 3-Gilead’s newly-acquired Sofosbuvir, GS-7977 shines in Hepatitis C trial
Sofosbuvir
Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
The Foster City, CA-based Gilead said that its experimental drug GS-7977, originally known as PSI-7977 before the acquisition, when combined with ribavirin, cured a group of genotype 1 hepatitis C patients after four weeks of treatment. The clinical study involved hepatitis C patients who either failed to respond to previous therapies or had not been treated before. The genotype 1 is the most common form of HCV in the United States. It affects 70 to 90 percent of the people in this country who have hepatitis C.
Norbert Bischofberger, chief scientific officer at Gilead said patients with genotype 1 hepatitis C had no detectable signs of the virus after treated with GS-7977 combination therapy for a course of close to a month. Previous study showed the drug candidate could also cure patients with genotype 2 and 3 HCV.
Gilead gained rights to GS-7977 through the $11 billion Pharmasset acquisition deal, which enable the company to be in an advanced position to compete with a few pharma companies seeking to develop an all-oral regimen for hepatitis C. The 100 percent cure rate data suggested that GS-7977 may be one of the most promising therapies for hepatitis C.
Last year, GS-7977, an oral uridine nucleotide analog polymerase inhibitor of HCV, received fast track designation from the U.S. FDA for the treatment of HCV infection.
The World Health Organization estimated that 3–4 million people are infected with HCV each year. Some 130–170 million people are chronically infected with HCV and at risk of developing liver cirrhosis and/or liver cancer, and more than 350,000 people die yearly from hepatitis C-related diseases.
Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.[2]
Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.[3]
Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.
Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[6]
- Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
- “PSI-7977”. Gilead Sciences.
- Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977”. Journal of Biological Chemistry 285 (45): 34337–34347. doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
- Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
- Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
- http://www.gilead.com/pr_1757156
- AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
- Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
- CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
New Drug Approvals 