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Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease
R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001
Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).
FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020
Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.
“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”
Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.
Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.
The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.
The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.
Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).
The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.
Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, non-small cell lung cancer and sarcoma. Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.
Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials. It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema. It was granted Breakthrough Therapy, Orphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.
In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis. In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED. On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.
Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.
Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo. Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation. The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.
- “FDA approves first treatment for thyroid eye disease”. U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020. This article incorporates text from this source, which is in the public domain.
- Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”. The New England Journal of Medicine. 376 (18): 1748–1761. doi:10.1056/NEJMoa1614949. PMC 5718164. PMID 28467880.
- “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”. Horizon Pharma plc. Retrieved 22 March 2019.
- “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”. Horizon Therapeutics plc. Retrieved 27 August 2019.
- “Teprotumumab”. Drug Information Portal. U.S. National Library of Medicine.
|Other names||teprotumumab-trbw, RG-1507|
|Chemical and physical data|
|Molar mass||145.6 kg/mol g·mol−1|
/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza, Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS, active thyroid eye disease, Teprotumumab
Brilliant blue G
FDA 2019, 12/20/2019, TISSUEBLUE, New Drug Application (NDA): 209569
Company: DUTCH OPHTHALMIC, PRIORITY; Orphan
OPQ recommends APPROVAL of NDA 209569 for commercialization of TissueBlue (Brilliant Blue G Ophthalmic Solution), 0.025%
ブリリアントブルーG, C.I. Acid Blue 90
Brilliant Blue G
Derma Cyanine G
////////////Brilliant blue G , ブリリアントブルーG , C.I. Acid Blue 90, FDA 2019, PRIORITY, Orphan
- Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, hydroxide, inner salt, monosodium salt
- Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, inner salt, monosodium salt (9CI)
- Brilliant Indocyanine G (6CI)
- C.I. Acid Blue 90 (7CI)
- C.I. Acid Blue 90, monosodium salt (8CI)
- Acid Blue 90
- Acid Blue G 4061
- Acid Blue PG
- Acid Bright Blue G
- Acid Brilliant Blue G
- Acid Brilliant Cyanine G
- Acidine Sky Blue G
- Amacid Brilliant Cyanine G
- Anadurm Cyanine A-G
- Benzyl Cyanine G
- Biosafe Coomassie Stain
- Boomassie blue silver
- Brilliant Acid Blue G
- Brilliant Acid Blue GI
- Brilliant Acid Blue J
- Brilliant Acid Cyanine G
- Brilliant Blue G
- Brilliant Blue G 250
- Brilliant Blue J
- Brilliant Indocyanine GA-CF
- Bucacid Brilliant Indocyanine G
- C.I. 42655
- CBB-G 250
- Colocid Brilliant Blue EG
- Coomassie Blue G
- Coomassie Blue G 250
- Coomassie Brilliant Blue G
- Coomassie Brilliant Blue G 250
- Coomassie G 250
- Cyanine G
- Daiwa Acid Blue 300
- Derma Cyanine G
- Derma Cyanine GN 360
- Dycosweak Acid Brilliant Blue G
- Eriosin Brilliant Cyanine G
- Fenazo Blue XXFG
- Impero Azure G
- Kayanol Cyanine G
- Lerui Acid Brilliant Blue G
- Milling Brilliant Blue 2J
- NSC 328382
- Optanol Cyanine G
- Orient Water Blue 105
- Orient Water Blue 105S
- Polar Blue G
- Polar Blue G 01
- Polycor Blue G
- Sandolan Cyanine N-G
- Sellaset Blue B
- Serva Blue G
- Serva Blue G 250
- Silk Fast Cyanine G
- Simacid Blue G 350
- Sumitomo Brilliant Indocyanine G
- Supranol Cyanin G
- Supranol Cyanine G
- Triacid Fast Cyanine G
- Water Blue 105
- Water Blue 105S
- Water Blue 150
- Xylene Brilliant Cyanine G
Antineoplastic, Tyrosine kinase inhibitor
|No.||Drug Name||Active Ingredient||Approval Date||FDA-approved use on approval date*|
|1.||Ayvakit||avapritinib||1/9/2020||To treat adults with unresectable or metastatic gastrointestinal stromal tumor (GIST)|
PRIORITY; Orphan, NDA 212608
Avapritinib, sold under the brand name Ayvakit, is a medication used for the treatment of tumors due to one specific rare mutation: It is specifically intended for adults with unresectable or metastatic ( y) gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.
Common side effects are edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash. and dizziness.
The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020. The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation. The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.
Avapritinib was approved based on the results from the Phase I NAVIGATOR clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation. Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response. For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response. While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).
Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)
Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:
4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na2S04, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C25H22FN90 requires: 483, found: 484 [M + H]+.
Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:
(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l- methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5- yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C29H3iFN10OS requires: 586, found: 587 [M + H]+.
Step 3: Synthesis of (lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-
(lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C3oH35FN10OS requires: 602, found: 603 [M + H]+. Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:
(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1- /] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4- yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C26H27FN10requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]+.
Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- 1 -yl)pyrimidin- -yl)ethanamine:
The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH- pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (lS,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)
C26H27FN10 requires: 498, found: 499 [M + H]+.
- “FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors”. U.S. Food and Drug Administration (FDA) (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020. This article incorporates text from this source, which is in the public domain.
- “Blueprint Medicines Announces FDA Approval of AYVAKIT (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor”. Blueprint Medicines Corporation (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020.
- “Blueprint Medicines Announces Updated NAVIGATOR Trial Results in Patients with Advanced Gastrointestinal Stromal Tumors Supporting Development of Avapritinib Across All Lines of Therapy”. Blueprint Medicines Corporation (Press release). 15 November 2018. Archived from the original on 10 January 2020. Retrieved 9 January 2020.
- Wu CP, Lusvarghi S, Wang JC, et al. (July 2019). “Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines”. Mol. Pharm. 16 (7): 3040–3052. doi:10.1021/acs.molpharmaceut.9b00274. PMID 31117741.
- Gebreyohannes YK, Wozniak A, Zhai ME, et al. (January 2019). “Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors”. Clin. Cancer Res. 25 (2): 609–618. doi:10.1158/1078-0432.CCR-18-1858. PMID 30274985.
|Other names||BLU-285, BLU285|
|Drug class||Antineoplastic agents|
|Chemical and physical data|
|Molar mass||498.570 g·mol−1|
|3D model (JSmol)|
///////Avapritinib, 2020 APPROVALS, PRIORITY, Orphan, BLU-285, BLU285, FDA 2020, Ayvakit, アバプリチニブ , авапритиниб , أفابريتينيب ,
Sickle cell disease is a lifelong, inherited blood disorder in which red blood cells are abnormally shaped (in a crescent, or “sickle” shape), which restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. It is also characterized by severe and chronic inflammation that worsens vaso-occlusive crises during which patients experience episodes of extreme pain and organ damage. Nonclinical studies have demonstrated that Oxbryta inhibits red blood cell sickling, improves red blood cell deformability (ability of a red blood cell to change shape) and improves the blood’s ability to flow.
“Oxbryta is an inhibitor of deoxygenated sickle hemoglobin polymerization, which is the central abnormality in sickle cell disease,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research. “With Oxbryta, sickle cells are less likely to bind together and form the sickle shape, which can cause low hemoglobin levels due to red blood cell destruction. This therapy provides a new treatment option for patients with this serious and life-threatening condition.”
Oxbryta’s approval was based on the results of a clinical trial with 274 patients with sickle cell disease. In the study, 90 patients received 1500 mg of Oxbryta, 92 patients received 900 mg of Oxbryta and 92 patients received a placebo. Effectiveness was based on an increase in hemoglobin response rate in patients who received 1500 mg of Oxbryta, which was 51.1% for these patients compared to 6.5% in the placebo group.
- Anavex 2-73
- AE-37 / AE37 / ANAVEX 2-73 FREE BASE
- UNII 9T210MMZ3F
Treatment of Rett syndrome, Investigated for use/treatment in breast cancer.
Anti-amnesic, Muscarinic/sigma receptor agonist
- Originator Anavex Life Sciences
- Developer ABX-CRO; Anavex Life Sciences; The Michael J. Fox Foundation for Parkinsons Research
- Class Antidementias; Antidepressants; Antiepileptic drugs; Antiparkinsonians; Anxiolytics; Behavioural disorder therapies; Dimethylamines; Furans; Neuroprotectants; Neuropsychotherapeutics; Nootropics; Small molecules
- Mechanism of Action Muscarinic receptor modulators; Sigma-1 receptor agonists
- Orphan Drug Status Yes – Epilepsy; Rett syndrome
- Phase II/III Alzheimer’s disease
- Phase II Parkinson’s disease; Rett syndrome
- Preclinical Amyotrophic lateral sclerosis; Angelman syndrome; Anxiety disorders; Autistic disorder; Fragile X syndrome; Multiple sclerosis
- No development reported Cognition disorders; Epilepsy; Stroke
- 28 Oct 2019 No recent reports of development identified for phase-I development in Cognition-disorders in USA
- 09 Oct 2019 Anavex Life Sciences initiates enrolment in the long term extension ATTENTION-AD trial for Alzheimer’s disease in (country/ies)
- 02 Oct 2019 Anavex Life Sciences has patent protection covering compositions of matter and methods of treating Alzheimer’s disease for blarcamesine in USA
- Anavex Life Sciences is developing ANAVEX-2-73 and its active metabolite ANAVEX-19-144, for treating Alzheimer’s disease, epilepsy, stroke and Rett syndrome.
ANAVEX2-73 is an experimental drug is in Phase II trials for Alzheimer’s disease, phase I trials for epilepsy, and in preclinical trials for amyotrophic lateral sclerosis, Parkinson’s disease, Rett syndrome, stroke. ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist. ANAVEX2-73 may function as a pro-drug for ANAVEX19-144 as well as a drug itself. ANAVEX19-144 is the active metabolite of ANAVEX 1-41, which is similar to ANAVEX2-73 but it is not as selective for sigma receptor.
Properties and uses
ANAVEX2-73 has an inhibitory constant (ki) lower than 500 nM for all M1–M4 muscarinic acetylcholine receptor subtypes, demonstrating that it acts as a powerful antimuscarinic compound. ANAVEX2-73 was originally tested in mice against the effect of the muscarinic receptor antagonist scopolamine, which induces learning impairment. M1 receptor agonists are known to reverse the amnesia caused by scopolamine. Scopolamine is used in the treatment of Parkinson’s disease and motion sickness by reducing the secretions of the stomach and intestines and can also decreases nerve signals to the stomach. This is via competitive inhibition of muscarinic receptors. Muscarinic receptors are involved in the formation of both short term and long term memories. Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta and target GSK-3B.[clarification needed]Furthermore, stimulation of the M1 receptor activates AF267B, which in turn blocks β-secretase, which cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme[clarification needed] is involved in the formation of Tau plaques, which are common in Alzheimer’s disease.[clarification needed]Therefore. M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.
Sigma1 activation appears to be only involved in long-term memory processes. This partly explains why ANAVEX2-73 seems to be more effective in reversing scopolamine-induced long-term memory problems compared to short-term memory deficits. The sigma-1 receptor is located on mitochondria-associated endoplasmic reticulum membranes and modulates the ER stress response and local calcium exchanges with the mitochondria. ANAVEX2-73 prevented Aβ25-35-induced increases in lipid peroxidation levels, Bax/Bcl-2ratio and cytochrome c release into the cytosol, which are indicative of elevated toxicity.[clarification needed] ANAVEX2-73 inhibits mitochondrial respiratory dysfunction and therefore prevents against oxidative stress and apoptosis. This drug prevented the appearance of oxidative stress. ANAVEX2-73 also exhibits anti-apoptotic and anti-oxidant activity. This is due in part because sigma-1 agonists stimulate the anti-apoptoic factor Bcl-2 due to reactive oxygen species dependent transcriptional activation of nuclear factor kB. Results from Marice (2016) demonstrate that sigma1 compounds offer a protective potential, both alone and possibly with other agents like donepezil, an acetylcholinesterase inhibitor, or the memantine, a NMDA receptor antagonist.
Novel crystalline forms of A2-73 (blarcamesine hydrochloride, ANAVEX2-73, AV2-73), a mixed muscarinic receptor ligand and Sig-1 R agonist useful for treating Alzheimer’s disease.
By Foscolos, George B. et alFrom Farmaco, 51(1), 19-26; 1996
- “ANAVEX 2-73 – AdisInsight”. Adisinsight.springer.com. Retrieved 2016-05-25.
- Malviya, M; Kumar, YC; Asha, D; Chandra, JN; Subhash, MN; Rangappa, KS (2008). “Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer’s presenile dementia models”. Bioorg Med Chem. 16: 7095–7101. doi:10.1016/j.bmc.2008.06.053.
- Leal, NS; Schreiner, B; Pinho, CM; Filadi, R; Wiehager, B; Karlström, H; Pizzo, P; Ankarcrona, M (2016). “Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid β-peptide production”. J Cell Mol Med. 20: 1686–1695. doi:10.1111/jcmm.12863. PMC 4988279. PMID 27203684.
- Lahmy, V; Long, R; Morin, D; Villard, V; Maurice, T (2015-09-28). “Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25-35 peptide-injected mice, a nontransgenic Alzheimer’s disease model”. Front Cell Neurosci. 8: 463. doi:10.3389/fncel.2014.00463. PMC 4299448. PMID 25653589.
- Maurice, T (2015-09-28). “Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments”. Behav. Brain Res. 296: 270–8. doi:10.1016/j.bbr.2015.09.020. PMID 26386305.
//////////Blarcamesine, ブラルカメシン , Orphan Drug Status, PHASE 2
FDA approves treatment Inrebic (fedratinib) for patients with rare bone marrow disorder
Today, the U.S. Food and Drug Administration approved Inrebic (fedratinib) capsules to treat adult patients with certain types of myelofibrosis.
“Prior to today, there was one FDA-approved drug to treat patients with myelofibrosis, a rare bone marrow disorder. Our approval today provides another option for patients,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The FDA is committed to encouraging the development of treatments for patients with rare diseases and providing alternative options, as not all patients respond in the same way.”
Myelofibrosis is a chronic disorder where scar tissue forms in the bone marrow and the production of the blood cells moves from the bone marrow to the spleen and liver, causing organ enlargement. It can cause extreme fatigue, shortness of breath, pain below the ribs, fever, night sweats, itching and bone pain. When myelofibrosis occurs on its own, it is called primary myelofibrosis. Secondary myelofibrosis occurs when there is excessive red blood cell production (polycythemia vera) or excessive platelet production (essential thrombocythemia) that evolves into myelofibrosis.
Jakafi (ruxolitinib) was approved by the FDA in 2011. The approval of Inrebic for intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis was based on the results of a clinical trial where 289 patients with myelofibrosis were randomized to receive two different doses (400 mg or 500 mg daily by mouth) of fedratinib or placebo. The clinical trial showed that 35 of 96 patients treated with the fedratinib 400 mg daily dose (the dose recommended in the approved label) experienced a significant therapeutic effect (measured by greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 (week 24) as measured by an MRI or CT scan with a follow-up scan four weeks later). As a result of treatment with Inrebic, 36 patients experienced greater than or equal to a 50% reduction in myelofibrosis-related symptoms, such as night sweats, itching, abdominal discomfort, feeling full sooner than normal, pain under ribs on left side, and bone or muscle pain.
The prescribing information for Inrebic includes a Boxed Warning to advise health care professionals and patients about the risk of serious and fatal encephalopathy (brain damage or malfunction), including Wernicke’s, which is a neurologic emergency related to a deficiency in thiamine. Health care professionals are advised to assess thiamine levels in all patients prior to starting Inrebic, during treatment and as clinically indicated. If encephalopathy is suspected, Inrebic should be immediately discontinued.
Common side effects for patients taking Inrebic are diarrhea, nausea, vomiting, fatigue and muscle spasms. Health care professionals are cautioned that patients may experience severe anemia (low iron levels) and thrombocytopenia (low level of platelets in the blood). Patients should be monitored for gastrointestinal toxicity and for hepatic toxicity (liver damage). The dose should be reduced or stopped if a patient develops severe diarrhea, nausea or vomiting. Treatment with anti-diarrhea medications may be recommended. Patients may develop high levels of amylase and lipase in their blood and should be managed by dose reduction or stopping the mediation. Inrebic must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.
The FDA granted this application Priority Review designation. Inrebic also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly-owned subsidiary of Celgene Corporation.
FDA approves third oncology drug Rozlytrek (entrectinib) that targets a key genetic driver of cancer, rather than a specific type of tumor
FDA also approves drug for second indication in a type of lung cancer
The U.S. Food and Drug Administration today granted accelerated approval to Rozlytrek (entrectinib), a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.
“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” said FDA Acting Commissioner Ned Sharpless, M.D. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”
This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated. The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.” It follows the policies that the FDA developed in a guidance document released in 2018. The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.
“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”
The ability of Rozlytrek to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for nine months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.
Rozlytrek was also approved today for the treatment of adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic). Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.
Rozlytrek’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects of Rozlytrek are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with Rozlytrek. Women who are pregnant or breastfeeding should not take Rozlytrek because it may cause harm to a developing fetus or newborn baby.
Rozlytrek was granted accelerated approval. This approval commits the sponsor to provide additional data to the FDA. Rozlytrek also received Priority Review, Breakthrough Therapy and Orphan Drug designation. The approval of Rozlytrek was granted to Genentech, Inc.
- CC 930
- A c-Jun amino-terminal kinase inhibitor.UNII, M5O06306UO
Treatment of Idiopathic Pulmonary Fibrosis (IPF)
- Originator Celgene Corporation
- Class Antifibrotics; Small molecules
- Mechanism of ActionJ NK mitogen-activated protein kinase inhibitors
- Orphan Drug Status Yes – Idiopathic pulmonary fibrosis
- Discontinued Discoid lupus erythematosus; Idiopathic pulmonary fibrosis
- 16 Jul 2012 Celgene Corporation terminates a phase II trial in Discoid lupus erythematosus in USA (NCT01466725)
- 23 Feb 2012 Celgene initiates enrolment in a phase II trial for Discoid lupus erythematosus in the USA (NCT01466725)
- 08 Nov 2011The Committee for Orphan Medicinal Products (COMP) recommends orphan drug designation for tanzisertib in European Union for Idiopathic pulmonary fibrosis
Tanzisertib has been granted orphan drug status by the FDA for the treatment of idiopathic pulmonary fibrosis. A positive opinion has been received from the EU Committee for Orphan Medicinal Products (COMP
Tanzisertib has been used in trials studying the treatment of Fibrosis, Discoid Lupus, Pulmonary Fibrosis, Interstitial Lung Disease, and Lung Diseases, Interstitial, among others.
/////////Tanzisertib, CC 930, Idiopathic Pulmonary Fibrosis, Orphan Drug, phase II, CELGENE