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FDA approves a new drug Xofluza (baloxavir marboxil) to treat influenza

October 25, 2018 1:27 am / Leave a comment

FDA approves a new drug to treat influenza

Today, the U.S. Food and Drug Administration approved Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm?utm_campaign=10242018_PR_FDA%20approves%20a%20new%20drug%20to%20treat%20influenza&utm_medium=email&utm_source=Eloqua

October 24, 2018

Release

Español

“This is the first new antiviral flu treatment with a novel mechanism of action approved by the FDA in nearly 20 years. With thousands of people getting the flu every year, and many people becoming seriously ill, having safe and effective treatment alternatives is critical. This novel drug provides an important, additional treatment option,” said FDA Commissioner Scott Gottlieb, M.D. “While there are several FDA-approved antiviral drugs to treat flu, they’re not a substitute for yearly vaccination. Flu season is already well underway, and the U.S. Centers for Disease Control and Prevention recommends getting vaccinated by the end of October, as seasonal flu vaccine is one of the most effective and safest ways to protect yourself, your family and your community from the flu and serious flu-related complications, which can result in hospitalizations. Yearly vaccination is the primary means of preventing and controlling flu outbreaks.”

Flu is a contagious respiratory illness caused by influenza viruses. When patients with the flu are treated within 48 hours of becoming sick, antiviral drugs can reduce symptoms and duration of the illness.

“When treatment is started within 48 hours of becoming sick with flu symptoms, antiviral drugs can lessen symptoms and shorten the time patients feel sick,” said Debra Birnkrant, M.D., director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Having more treatment options that work in different ways to attack the virus is important because flu viruses can become resistant to antiviral drugs.”

The safety and efficacy of Xofluza, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 patients where participants were assigned to receive either Xofluza, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms. In both trials, patients treated with Xofluza had a shorter time to alleviation of symptoms compared with patients who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received Xofluza and those who received the other flu treatment.

The most common adverse reactions in patients taking Xofluza included diarrhea and bronchitis.

Xofluza was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted approval of Xofluza to Shionogi & Co., Ltd.

//////////////Xofluza, baloxavir marboxil, FDA 2018

USFDA approval to Lumoxiti (moxetumomab pasudotoxtdfk) a new treatment for hairy cell leukemia

October 24, 2018 11:11 am / Leave a comment

Image result for moxetumomab pasudotox tdfk

USFDA approval to Lumoxiti is a new treatment for hairy cell leukemia

On September 13, 2018, the U.S. Food and Drug Administration approved Lumoxiti (moxetumomab pasudotoxtdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory Hairy Cell Leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog 1. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL. The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent. The FDA granted this application Fast Track and Priority Review designations. Lumoxiti 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 Lumoxiti to AstraZeneca Pharmaceuticals. About Hairy Cell Leukemia HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cells that fight infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

About Lumoxiti2 Lumoxiti (moxetumomab pasudotox) is a CD22-directed cytotoxin and a first-in-class treatment in the US for adult patients with relapsed or refractory hairy cell leukaemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is not recommended in patients with severe renal impairment (CrCl ≤ 29 mL/min). It comprises the CD22 binding portion of an antibody fused to a truncated bacterial toxin; the toxin inhibits protein synthesis and ultimately triggers apoptotic cell death.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” 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. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

The FDA granted this application Fast Track and Priority Review designations. Lumoxiti 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 Lumoxiti to AstraZeneca Pharmaceuticals.

1 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620448.htm

2 https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-lumoxiti-moxetumomab-pasudotox-tdfk-for-certain-patientswith-relapsed-or-refractory-hairy-cell-leukaemia.html

/////////// Lumoxiti, moxetumomab pasudotoxtdfk, FDA 2018, Fast Track, Priority Review , Orphan Drug, AstraZeneca

FDA approves first treatment Libtayo (cemiplimab-rwlc) for advanced form of the second most common skin cancer

October 7, 2018 4:21 am / Leave a comment

FDA approves first treatment for advanced form of the second most common skin cancer

New drug targets PD-1 pathway

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM622044.htm?utm_campaign=09282018_PR_FDA%20approves%20treatment%20for%20metastatic%20cutaneous%20squamous%20cell%20carcinoma&utm_medium=email&utm_source=Eloqua

September 28, 2018

Release

Libtayo works by targeting the cellular pathway known as PD-1 (protein found on the body’s immune cells and some cancer cells). By blocking this pathway, the drug may help the body’s immune system fight the cancer cells.

“We’re continuing to see a shift in oncology toward identifying and developing drugs aimed at a specific molecular target. With the Libtayo approval, the FDA has approved six immune checkpoint inhibitors targeting the the PD-1 / PD-L1 pathway for treating a variety of tumors, from bladder to head and neck cancer, and now advanced CSCC,” 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. “This type of cancer can be difficult to treat effectively when it is advanced and it is important that we continue to bring new treatment options to patients.”

CSCC is the second most common human cancer in the United States with an estimated annual incidence of approximately 700,000 cases. The most common form of skin cancer is basal cell cancer. Squamous cells are thin, flat cells that look like fish scales and are found in the tissue that forms the surface of the skin. CSCC usually develops in skin areas that have been regularly exposed to the sun or other forms of ultraviolet radiation. While the majority of patients with CSCC are cured with surgical resection, a small percentage of patients will develop advanced disease that no longer responds to local treatments including surgery and radiation. Advanced CSCC may cause disfigurement at the site of the tumor and local complications such as bleeding or infection, or it may spread (metastasize) to local lymph nodes, distant tissues and organs and become life-threatening.

The safety and efficacy of Libtayo was studied in two open label clinical trials. A total of 108 patients (75 with metastatic disease and 33 with locally-advanced disease) were included in the efficacy evaluation. The study’s primary endpoint was objective response rate, or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) after treatment. Results showed that 47.2 percent of all patients treated with Libtayo had their tumors shrink or disappear. The majority of these patients had ongoing responses at the time of data analysis.

Common side effects of Libtayo include fatigue, rash and diarrhea. Libtayo must be dispensed with a patient Medication Guide that describes uses of the drug and its serious warnings. Libtayo can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These reactions can sometimes become severe or life-threatening and can lead to death. These reactions include the risk of immune-mediated adverse reactions including lung problems (pneumonitis), intestinal problems (colitis), liver problems (hepatitis), hormone gland problems (endocrinopathies), skin (dermatologic) problems and kidney problems. Patients should also be monitored for infusion-related reactions.

Libtayo can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignations.

The FDA granted the approval of Libtayo to Regeneron Pharmaceuticals, Inc.

////////////Libtayo, cemiplimab-rwlc, FDA 2018, Breakthrough Therapy, Priority Review

Sarecycline , サレサイクリン

October 4, 2018 1:00 pm / Leave a comment

ChemSpider 2D Image | Sarecycline | C24H29N3O8

Sarecycline

サレサイクリン

MW 487.5024, MF C24H29N3O8 FREE FORM

Paratek INNOVATOR

FDA 2018/10/1 APPROVED SEYSARA, ALMIRALL, for the oral treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older

(4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-[(methoxymethylamino)methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-{[methoxy(methyl)amino]methyl}-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide

1035654-66-0 [RN] FREE FORM

2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-[(methoxymethylamino)methyl]-1,11-dioxo-, (4S,4aS,5aR,12aS)-

94O110CX2E

9743

P005672,

P 005672

Sarecycline hydrochloride.png

CAS 1035979-44-2 HCl

Molecular Formula	C24 H29 N3 O8 . Cl H
Molecular Weight	523.963

P-005672
PTK-AR-01
SC-1401
WC-3035

Sarecycline (trade name Seysara; development code WC-3035) is a tetracycline-derived antibiotic. In the United States, it was approved by the FDA in October 2018 for the treatment of moderate to severe acne vulgaris.^[1]

Paratek Pharmaceuticals, Inc. licensed the US rights to sarecycline for the treatment of acne in the United States to Actavis, a subsidiary of Allergan, while retaining rights in the rest of the world.^[2]

Allergan initiated a Phase 3 study in December 2014 evaluating the efficacy and safety of sarecycline tablets 1.5 mg/kg per day taken orally for 12 weeks versus placebo in the treatment of acne vulgaris.^[3] Two phase 3 randomized, multi-center, double-blind, placebo-controlled studies evaluating the efficacy and safety of sarecycline in moderate to severe acne reported positive results on 27 March 2017.^[4]

SYN

US 2016/0200671

PATENT

WO 2008079363

PATENT

WO 2008079339

PATENT

WO 2012155146

EXAMPLES

[00104] The following examples illustrate the synthesis of the compounds described herein.

Synthesis of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide (“the free base”).

[00105] A solution of 7-formylsancycline TFA salt (2.23 g) and N,0-dimethylhydroxylamine hydrochloride (780 mg) in N,N-dimethylacetamide (15 mL) was stirred for 10 minutes at room temperature under argon atmosphere. To this solution was added sodium cyanoborohydride (302 mg). The solution was stirred for 5 minutes and monitored by LC-MS. The reaction mixture was poured into diethyl ether, and the resulting precipitates were collected by filtration under vacuum. The crude product was purified by prep-HPLC using a C18 column (linear gradient 10-40% acetonitrile in 20 mM aqueous triethanolamine, pH 7.4). The prep-HPLC fractions were collected, and the organic solvent (acetonitrile) was evaporated under reduced pressure. The resulting aqueous solution was loaded onto a clean PDVB SPE column, washed with distilled water, then with a 0.1 M sodium acetate solution followed by distilled water. The product was eluted with

acetonitrile. The eluent was concentrated under reduced pressure, 385 mg was obtained as free base.

Synthesis of crystalline mono hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide (the “Crystalline Mono Hydrochloride Salt”).

[00106] Crude (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l ,ll-dioxo-l,4,4a,5,5a,6,l l ,12a-octahydro-naphthacene-2-carboxylic acid amide (lOOg, app. 35% assay) was purified on preparative column chromatography. The desired fractions (8-10 liters) were combined and the pH was adjusted to 7.0-7.5 using ammonium hydroxide. This aqueous solution was extracted 3 times with dichloromethane (4 liters each time). The dichloromethane layers were combined and concentrated under reduced pressure. The residue was suspended in ethanol (800 ml) and 20 ml water was added. The pH was gradually adjusted to pH 1.6-1.3 using 1.25M hydrochloric acid in methanol and the mixture was stirred for 20-60 minutes at which point the free base was completely dissolved. The solution was concentrated under reduced pressure to 200-250 ml and was seeded with (4S,4aS,5aR,12aS)-4-dimethylamino-3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono HQ crystals (100-200 mg). The stirring was continued for 2-18 hours while the slurry was kept at <5°C. The resulting crystals were filtered, washed with ethanol (50 mL) and dried under reduced pressure to a constant weight. 20g crystalline (4S,4aS,5aR,12aS)-4-dimethylamino-3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono hydrochloride was isolated in > 90% purity and > 90% assay.

Synthesis of crystalline mono mesylate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid (the “Crystalline Mesylate Salt”).

[00107] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (74mg) was suspended in ethanol (740μ1) and heated with stirring to 60°C (bath temperature). Methane sulfonic acid (1.1 eq, 167μ1 as 1M solution in THF) was added and most of the solid dissolved. After five minutes, the suspension was cooled to ambient temperature over approximately 1.75 hours (uncontrolled in oil bath). By 53 °C, solid had precipitated which was filtered at ambient temperature under reduced pressure. A further portion of ethanol (200μ1) was added to aid filtration, as the suspension was viscous. The cake was washed with n-hexane (400μ1) and air dried on filter for approximately 30 minutes to yield 59 mg (67% yield) of yellow solid.

Synthesis of crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid (the “Crystalline Sulfate Salt”).

[00108] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (86mg) was suspended in ethanol (500μ1) and heated with stirring to 63 °C (bath temperature) at which temperature most of the free base had dissolved. Sulfuric acid (1.1 eq, 194μ1 as 1M solution in water) was added and all of the solid dissolved. The solution was cooled to ambient temperature over approximately 1.75 hours (uncontrolled in oil bath) at which temperature no solid had precipitated. Methyl t-butyl ether (MtBE) was added as an antisolvent (4 x 50μ1). Each addition caused a cloud point, but the solid re-dissolved on stirring. The solution was stirred with a stopper for approximately 3 hours after which time solid precipitated. The solid was filtered under reduced pressure and washed with MtBE (3 x 200μ1) and air dried on filter for

approximately 45 minutes to yield 93 mg (90% yield) of yellow solid.

COMPARATIVE EXAMPLE 1

Synthesis of amorphous bis hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide.

[00109] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (1 g) was suspended in methanol (50 mL). The freebase was converted to the hydrochloride salt by adding an excess of methanolic HCl followed by under reduced pressure evaporation to give 1.1 g yellow solid: MS (Mz+1 = 488). 1H NMR (300 MHz, CD30D) δ 7.46 (d, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 8.6 Hz), 4.09 (d, 1H, J = 1.0 Hz), 3.79 (d, 1H, J = 13.1 Hz), 3.73 (d, 1H, J = 13.1 Hz), 3.36 (m, 1H), 3.27 (s, 3H), 3.08-2.95 (8H), 2.61 (s, 3H), 2.38 (t, 1H, J = 14.8), 2.22 (m, 1H), 1.64 (m, 1H). An XRPD pattern is shown in Figure 10 and a TGA and DSC curve overlaid are shown in Figure 11.

COMPARATIVE EXAMPLE 2

Synthesis of amorphous mono hydrochloride salt of (4S,4aS,5aR,12aS)-4- dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll- dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide.

[00110] A sample of Crystalline Mono Hydrochloride Salt (2.09 g) was dissolved in water (250 ml, 120 vols), filtered and frozen in a -78°C bath. Water was removed from the solidified sample using a lyophilizer for 110 hours to yield the amorphous mono hydrochloride salt as a fluffy yellow solid, that was confirmed to be amorphous by XRPD analysis .

PATENT

US 20130302442

PATENT

WO 2015153864

PATENT

WO 2018051102

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2003075857

References

Jump up^ “FDA Approves Sarecycline for Moderate to Severe Acne”. MedScape. October 2, 2018.
Jump up^ https://www.bloomberg.com/research/stocks/snapshot/snapshot_article.asp?ticker=N4CN:GR&txtsize=s
Jump up^ “Study to Evaluate Safety & Efficacy of Sarecycline in Treatment of Acne – Full Text View – ClinicalTrials.gov”.
Jump up^ “Allergan and Paratek Announce Positive Results From Two Phase 3 Trials of Sarecycline for the Treatment of Moderate to Severe Acne”. http://www.globenewswire.com. Retrieved 16 May 2017.

External links

Sarecycline – Almirall S.A./Paratek Pharmaceuticals, Adis Insight

Sarecycline
Clinical data

Trade names	Seysara
Identifiers
IUPAC name [show]
CAS Number	1035654-66-0
PubChem CID	71296095
ChemSpider	28540486
UNII	94O110CX2E
Chemical and physical data
Formula	C₂₄H₂₉N₃O₈
Molar mass	487.51 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CN(C)[C@H]1[C@@H]2C[C@@H]3CC4=C(C=CC(=C4C(=C3C(=O)[C@@]2(C(=C(C1=O)C(=O)N)O)O)O)O)CN(C)OC

////////////Sarecycline, Seysara, WC-3035 FDA 2018, サレサイクリン , P-005672 , PTK-AR-01 , SC-1401, WC-3035,

FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation

September 29, 2018 2:37 am / 1 Comment on FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation

FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation

First drug granted approval under FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs, instituted to spur development of antibiotics for unmet medical needs

The U.S. Food and Drug Administration today approved a new drug, Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC) in a limited population of patients with the disease who do not respond to conventional treatment (refractory disease).

MAC is a type of nontuberculous mycobacteria (NTM) commonly found in water and soil. Symptoms of disease in patients with MAC include persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood.

September 28, 2018

Release

“As bacteria continue to grow impervious to currently available antibiotics, we need to encourage the development of drugs that can treat resistant infections. That means utilizing novel tools intended to streamline development and encourage investment into these important endeavors,” said FDA Commissioner Scott Gottlieb, M.D. “This approval is the first time a drug is being approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, and it marks an important policy milestone. This pathway, advanced by Congress, aims to spur development of drugs targeting infections that lack effective therapies. We’re seeing a lot of early interest among sponsors in using this new pathway, and it’s our hope that it’ll spur more development and approval of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs.”

Arikayce is the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD pathway, established by Congress under the 21st Century Cures Act to advance development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Approval under the LPAD pathway may be supported by a streamlined clinical development program. These programs may involve smaller, shorter or fewer clinical trials. As required for drugs approved under the LPAD pathway, labeling for Arikayce includes certain statements to convey that the drug has been shown to be safe and effective only for use in a limited population.

Arikayce also was approved under the Accelerated Approval pathway. Under this approach, the FDA may approve drugs for serious or life-threatening diseases or conditions where the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The approval of Arikayce was based on achieving three consecutive negative monthly sputum cultures by month six of treatment. The sponsor of Arikayce will be required by the FDA to conduct an additional, post-market study to describe the clinical benefits of Arikayce.

The safety and efficacy of Arikayce, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. One group of patients received Arikayce plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone. By the sixth month of treatment, 29 percent of patients treated with Arikayce had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9 percent of patients who were not treated with Arikayce.

The Arikayce prescribing information includes a Boxed Warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases. Other common side effects in patients taking Arikayce were dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.

The FDA granted this application Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product (QIDP) designations. QIDP designation is given to antibacterial products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. Arikayce also received Orphan Drug designation, which provides additional incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Arikayce to Insmed, Inc. of Bridgewater, NJ.

/////////////////// Arikayce, amikacin liposome inhalation suspension, fda 2018, Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product, QIDP, Generating Antibiotic Incentives Now, GAIN,

Glycopyrrolate Tosylate

September 20, 2018 2:12 am / 1 Comment on Glycopyrrolate Tosylate

Glycopyrrolate Tosylate.png Figure US20130211101A1-20130815-C00001

Glycopyrrolate Tosylate

Molecular Formula:	C₂₆H₃₅NO₆S
Molecular Weight:	489.627 g/mol

(1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate;4-methylbenzenesulfonate

CAS 873295-46-6 , C₁₉ H₂₈ N O₃ . C₇ H₇ O₃ S, Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzenesulfonate (1:1)

Glycopyrronium tosylate monohydrate

Molecular Formula, C19-H28-N-O3.C7-H8-O3-S.H2-O, Molecular Weight, 508.6522

https://chem.nlm.nih.gov/chemidplus/structure/1624259-25-1?maxscale=30&width=300&height=300

CAS 1624259-25-1, C₁₉ H₂₈ N O₃ . C₇ H₇ O₃ S . H₂ O, Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzenesulfonate, hydrate (1:1:1)

Dermira (Originator)

DRM-04
DRM-04B

DRM-04 tosylate monohydrate
DRM04
DRM04 tosylate
Glycopyrronium tosylate
Glycopyrronium tosylate monohydrate
Glycopyrronium tosylate [USAN]
UNII-1PVF6JLU7B
UNII-X2N5209428

In 2018, the product was approved in the U.S. for the treatment of primary axillary hyperhidrosis in adult and pediatric patients 9 years of age and older.

In 2016, Maruho signed an exclusive license agreement with Dermina for product development and marketing in Japan for the treatment of axillary hyperhidrosis.

PATENT

https://patents.google.com/patent/US8558008B2/en

PATENT

https://patents.google.com/patent/US20130211101A1/en

Glycopyrrolate is a quaternary ammonium cation of the muscarinic anticholinergic group. Glycopyrrolate, typically as a bromide salt, has been used in the treatment of a variety of conditions including diarrhea (U.S. Pat. Nos. 6,214,792 and 5,919,760), urinary incontinence (U.S. Pat. Nos. 6,204,285 and 6,063,808), and anxiety (U.S. Pat. No. 5,525,347). Additionally, U.S. Pat. No. 5,976,499 discloses a method for diagnosing cystic fibrosis in a patient by, in part, stimulating sweat production through the injection of a glycopyrrolate solution into a patient. Glycopyrrolate has also been used for the treatment of hyperhidrosis in US 20100276329.
[0002]
Glycopyrrolate has previously been made available as a bromide salt or an acetate salt. The bromide salt of glycopyrrolate is sold as Rubinol®. The term “glycopyrrolate” as used in the label for Rubinol® refers to the bromide salt which is more formally referred to as glycopyrronium bromide.

- [0124]
  In a dark room, silver tosylate (3.5 g) was dissolved in water (˜100 mL) by sonication. The solution was heated to approximately 40° C. and additional water was added (˜15 mL). An equimolar amount of glycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) was added and immediately resulted in a yellow precipitate. The slurry was stirred at approximately 40° C. overnight, and then slowly cooled while stirring to ambient temperature. At ambient temperature, the solids were vacuum filtered and the wet cake was washed three times with approximately 10 mL of water. The mother liquor was collected and filtered two times through a 0.2 μm nylon filter with glass microfiber (GMF). A clear solution was observed after filtration and was lyophilized at approximately −50° C. After 6 days, a mixture of white, needle-like and slightly sticky, glassy solids was observed. Toluene (˜20 mL) was added, and the slurry was briefly sonicated and then stirred at ambient temperature. Additional toluene (˜80 mL) was added for easier stirring, and the mixture was allowed to stand at ambient conditions for 1 day. Solids of glycopyrrolate tosylate were collected by vacuum filtration and vacuum drying at ambient temperature for 1 day.

Example 7 Preparation of Glycopyrrolate Tosylate

- [0125]
  A slurry of equimolar amounts of glycopyrrolate acetate and p-toluenesulfonic acid was prepared in isopropanol (1 mL). The mixture was stirred at ambient temperature. Additional isopropanol (0.5 mL) was added to improve stirring, and the mixture was stirred overnight. Solids of glycopyrrolate tosylate were isolated by vacuum filtration and analyzed.

Example 8 Preparation of Glycopyrrolate Tosylate Form D

- [0126]
  Glycopyrrolate tosylate (1.0569 g) made from Example 6 was dissolved in 4 mL ACN/H₂O (50/50 vol/vol) by sonication. The solution was filtered through 0.2 μm nylon filter into a clean vial. The solvent was allowed to partially evaporate from an open vial under ambient conditions. Further evaporation was subsequently performed under nitrogen gas flow. A gel resulted which was vacuum dried at 40° C. for 1 day. Toluene (5 mL) was added and the mixture was sonicated for approximately 10 minutes causing white solids to precipitate. The mixture was stirred at ambient temperature for 1 day. The solids were isolated by vacuum filtration and the wet cake was washed with approximately 10 mL of toluene. The solids were vacuum dried at ambient temperature for 1 day. After vacuum drying the solids were placed in a vial which remained uncapped and placed inside a relative humidity chamber (˜97%). The chamber was placed inside an oven at 41° C. After 6 days, the solids were analyzed by XRPD showing Form D.

Example 9 Single Crystal Preparation of Form D

- [0127]
  Glycopyrrolate tosylate (54.9 mg) made from Example 6 was dissolved in EtOAc/DMF (87/13 vol/vol) at approximately 55° C. at 24 mg/ml. The solution was hot filtered through a 0.2 μm nylon filter into a pre-warmed vial. The vial containing the solution was first placed in a dry ice/acetone bath and then in a freezer (approximately −25 to −10° C.). After 3 days, the solution was re-heated to approximately 50° C. and additional EtOAc was added for 96/4 EtOAc/DMF (vol/vol) at 7 mg/ml. The solution was quickly removed from elevated temperature and placed in the freezer. Solids were isolated by decanting the solvent and drying the solids under ambient conditions.
- [0128]
  Single Crystal Data Collection
- [0129]
  A colorless chunk of C₂₆H₃₇NO₇S [C₇H₇O₃S, C₁₉H₂₈NO₃, H₂O] having approximate dimensions of 0.23×0.20×0.18 mm, was mounted on a fiber in random orientation. Preliminary examination and data collection were performed with Cu Kα radiation (λ=1.54184 Å) on a Rigaku Rapid II diffractometer equipped with confocal optics. Refinements were performed using SHELX97.

Example 10 Preparation of Dehydrated Form D

- [0130]
  A mixture of glycopyrrolate tosylate solids, including Form C and Form D, and a trace amount of silver tosylate was kept over P₂O₅at ambient temperature for 18 days. The resulting solids were composed of a mixture of dehydrated Form D with a trace of silver tosylate as shown by XRPD analysis.

Example 11 Preparation of Form C Glycopyrrolate Tosylate

- [0131]
  Glycopyrrolate tosylate Form D, containing trace amounts of Form C and silver tosylate, was heated on an Anton Paar TTK 450 stage and XRPD patterns were collected in situ in the range 3.5-26° (2θ). All heating steps were at approximately 10° C./min. The stage was heated in incremental steps of 20° C. from 25 to 125° C. At each step, an XRPD pattern was collected over approximately 4 minutes. The stage was then heated to 135° C. and an XRPD pattern was collected over approximately 16 minutes and after heating further to 145° C., a pattern was collected in approximately 31 minutes. The sample was subsequently cooled to 25° C. at approximately 24° C./min, upon which a final XRPD pattern was collected over approximately 16 min. The XRPD pattern of this final pattern was indexed as Form C.

Example 12 Preparation of Form C Glycopyrrolate Tosylate

- [0132]
  Glycopyrrolate tosylate Form D from Example 6 was heated to an approximate temperature in the range 143-149° C. under a continuous nitrogen purge for approximately 3.3 hours. The vial containing the solids was capped, placed on a lab bench and allowed to cool down to room temperature. At room temperature, the vial was placed in a jar containing P₂O₅. The sample was prepared for XRPD analysis under nitrogen which confirmed production of Form C.

Example 13 Preparation of Form C Glycopyrrolate Tosylate

- [0133]
  Glycopyrrolate tosylate (59.5 mg) from Example 6 was dissolved in acetone at approximately 50° C. at 27 mg/ml. The solution was hot filtered through a 0.2 μm nylon filter into a pre-warmed vial. The vial was capped and left on the hot plate which was subsequently turned off to allow the sample to cool slowly to ambient temperature. At ambient temperature the solution was stirred causing white solids to precipitate. The solids were isolated by vacuum filtration and the wet cake was washed with approximately 2 ml of acetone. XRPD analysis resulted in Form C.

Example 14 Amorphous Glycopyrrolate Tosylate

[0134]
Glycopyrrolate tosylate from Example 6 was melted and cooled repeatedly until the majority of the solids had the appearance of a glass by microscopy. XRPD analysis indicated that the “glassy” sample was observed to be amorphous. A 2.2% weight loss was observed by TGA from 25 to 250° C. of the amorphous glycopyrrolate tosylate. The onset of the glass transition temperature was measured at 11.6° C.

In a dark room, silver tosylate (3.5 g) was dissolved in water (~ 100 mL) by sonication. The solution was heated to approximately 40°C. and additional water was added (-15 mL). An equimolar amount of glycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) was added and imme diately resulted in a yellow precipitate. The slurry was stirred at approximately 40°C. overnight, and then slowly cooled while stirring to ambient temperature. At ambient tempera ture, the solids were vacuum filtered and the wet cake was washed three times with approximately 10 mL of water. The mother liquor was collected and filtered two times through a 0.2 pm nylon filter with glass microfiber (GMF). A clear solution was observed after filtration and was lyophilized at approximately -50°C. After 6 days, a mixture of white, needle-like and slightly sticky, glassy solids was observed. Toluene (-20 mL) was added, and the slurry was briefly sonicated and then stirred at ambient temperature. Additional toluene (-80 mL) was added for easier stirring, and the mix ture was allowed to stand at ambient conditions for 1 day. Solids of glycopyrrolate tosylate were collected by vacuum filtration and vacuum drying at ambient temperature for 1 day. Glycopyrrolate Tosylate.

PAtent

https://patents.google.com/patent/CN103159659A/en

Image result for Glycopyrronium bromide synthesis

glycopyrrolate (I)

Methyl ethyl ketone (20mL) IOOmL three-necked flask was added 8 (4.6g, 15mmol) was, at (Γ5 ° C was added dropwise dibromomethane (2.9g, 30mmol) in butanone (5 mL) was added dropwise completed, continued The reaction was stirred for 15min, and a white solid precipitated, was allowed to stand 36h at room temperature, filtered off with suction, the filter cake was sufficiently dried to give crude ketone was recrystallized twice to give a white powdery crystals I (3.9g, 66%) mp 191~193 ° C chromatographic purity 99.8% [HPLC method, mobile phase: lmol / L triethylamine acetate – acetonitrile – water (1: 150: 49); detection wavelength: 230nm, a measurement of the area normalization method] .MS m / z: 318 ( m-BrO 1HNMR (CD3OD) δ:! 1.33~1.38 (m, 2H), 1.55~1.70 (m, 6H), 2.11~2.21 (m, 1H), 2.67~2.80 (m, 1H), 3.02 (m, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.59~3.71 (m, 3H), 3.90 (dd, /=13.8,1H), 5.47 (m, 1H), 7.27 (t, 1H) , 7.35 (t, 2H), 7.62 (dd, 2H) .13C bandit R (DMSO) δ: 27.0, 27.4, 28.0, 31.3, 47.8, 53.8, 54.3, 66.0, 71.3, 74.6, 81.1, 126.9,128.7,129.3 , 143.2 17 5.00

Patent

https://patents.google.com/patent/WO2016204998A1/en

Image result for Glycopyrronium bromide synthesis

PAPER

https://link.springer.com/article/10.1007/s41981-018-0015-4

Journal of Flow Chemistry, pp 1–8| Cite as

Sequential α-lithiation and aerobic oxidation of an arylacetic acid – continuous-flow synthesis of cyclopentyl mandelic acid

Open Access

Communications

First Online: 09 August 2018

Image result for Glycopyrronium bromide synthesis

The medicinal properties of glycopyrronium bromide (glycopyrrolate, 4) were first identified in the late 1950s [1]. Glycopyrrolate is an antagonist of muscarinic cholinergic receptors and is used for the treatment of drooling or excessive salivation (sialorrhea) [2], excess sweating (hyperhidrosis) [3], and overactive bladder and for presurgery treatment. In addition, it has recently been introduced as an effective bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) for asthma patients [4]. Glycopyrrolate displays few side effects because it does not pass through the blood brain barrier. Cyclopentyl mandelic acid (CPMA, 1), or its corresponding ester derivatives, are key intermediates in the synthetic routes to 4. CPMA (1) reacts with 1-methyl-pyrrolidin-3-ol (2) to form tertiary amine 3. N-Methylation of 3 by methyl bromide gives quaternary ammonium salt glycopyrrolate 4 as a racemate (Scheme 1) [5].

Scheme 1

Synthesis of glycopyrrolate 4 from CPMA (1)

CPMA (1) is a synthetically challenging intermediate to prepare (Scheme 2). Routes A to D are most likely to be the commercially applied methods because these procedures are described in patents [5]. The published descriptions for the yields of 1 range from 28 to 56% for routes A to D. Ethyl phenylglyoxylate is reacted with cyclopentyl magnesium bromide to form an ester which is then hydrolyzed (route A) [6]. Phenylglyoxylic acid can be reacted in a similar manner with cyclopentyl magnesium bromide to directly form 1 (route B) [7]. Alternatively, the inverse addition of phenyl-Grignard reagent to cyclopentyl glyoxylic acid ester is reported (route C) [8]. Cyclopentyl glyoxylic acid ester can also be reacted with cyclopentadienyl magnesium bromide which is followed by an additional hydrogenation step with Pd/C and H₂ to afford 1 (route D) [9, 10].

Publication numberPriority datePublication dateAssigneeTitle

WO2014134510A1 *2013-02-282014-09-04Dermira, Inc.Glycopyrrolate salts

US8859610B22013-02-282014-10-14Dermira, Inc.Crystalline glycopyrrolate tosylate

US9006462B22013-02-282015-04-14Dermira, Inc.Glycopyrrolate salts

US20160052879A1 *2014-08-202016-02-25Dermira, Inc.Process for production of glycopyrronium tosylate

Family To Family Citations

WO2018026869A12016-08-022018-02-08Dermira, Inc.Processes for making, and methods of using, glycopyrronium compounds

Patent ID	Title	Submitted Date	Granted Date
US9440056	DEVICE AND METHOD FOR DISPENSING A DRUG	2015-09-29	2016-03-31
US2016058735	METHODS OF TREATING HYPERHIDROSIS	2015-08-27	2016-03-03

Patent ID	Title	Submitted Date	Granted Date
US2017157088	GLYCOPYRROLATE SALTS	2017-02-21
US9610278	Glycopyrrolate Salts	2016-01-07	2016-04-28
US2016052879	PROCESS FOR PRODUCTION OF GLYCOPYRRONIUM TOSYLATE	2015-08-19	2016-02-25
US9006461	CRYSTALLINE GLYCOPYRROLATE TOSYLATE	2013-09-11	2014-08-28
US2016243345	DEVICE AND METHOD FOR DISPENSING A DRUG	2016-05-04	2016-08-25

Patent ID	Title	Submitted Date	Granted Date
US2016354315	DOSAGE FORMS AND USE THEREOF	2016-06-03
US9259414	Glycopyrrolate Salts	2015-03-10	2015-07-16
US9006462	Glycopyrrolate Salts	2014-08-29	2014-12-18
US8558008	Crystalline glycopyrrolate tosylate	2013-02-28	2013-10-15
US8859610	Crystalline glycopyrrolate tosylate	2013-09-11	2014-10-14

Title: Glycopyrrolate

CAS Registry Number: 596-51-0

CAS Name: 3-[(Cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidinium bromide

Additional Names: 3-hydroxy-1,1-dimethylpyrrolidinium bromide a-cyclopentylmandelate; a-cyclopentylmandelic acid ester with 3-hydroxy-1,1-dimethylpyrrolidinium bromide; 1-methyl-3-pyrrolidyl a-cyclopentylmandelate methobromide; 1-methyl-3-pyrrolidyl a-phenyl-a-cyclopentylglycolate methobromide; 3-(2-phenyl-2-cyclopentylglycoloyloxy)-1,1-dimethylpyrrolidinium bromide; glycopyrronium bromide

Manufacturers’ Codes: AHR-504

Trademarks: Nodapton; Robanul; Robinul (Robins); Tarodyl; Tarodyn

Molecular Formula: C19H28BrNO3

Molecular Weight: 398.33

Percent Composition: C 57.29%, H 7.09%, Br 20.06%, N 3.52%, O 12.05%

Literature References: Synthetic, quaternary ammonium anticholinergic. Prepn: Franko, Lunsford, J. Med. Pharm. Chem.2, 523 (1960); Lunsford, US2956062 (1960 to A. H. Robins). Pharmacodynamics: E. Kaltiala et al.,J. Pharm. Pharmacol.26, 352 (1974). Toxicology: B. V. Franko et al.,Toxicol. Appl. Pharmacol.17, 361 (1970). Clinical comparison with atropine in anaesthetic practice: F. Kongsrud, S. Sponheim, Acta Anaesthesiol. Scand.26, 620 (1982); A. I. Webb, R. M. McMurphy, Am. J. Vet. Res.48, 1733 (1987); B. V. G. Malling et al.,Br. J. Anaesth.60, 426 (1988). Brief review of pharmacology and clinical use: R. K. Mirakhur, J. W. Dundee, Anaesthesia38, 1195-1204 (1983).

Properties: White crystals from butanone, mp 193.2-194.5°. Sol in water. LD50 (72 hr.) in female mice, female rats (mg/kg): 107, 196 i.p.; in male rats (mg/kg): 1150 orally (Franko).

Melting point: mp 193.2-194.5°

Toxicity data: LD50 (72 hr.) in female mice, female rats (mg/kg): 107, 196 i.p.; in male rats (mg/kg): 1150 orally (Franko)

Therap-Cat: Antispasmodic; preanesthetic medicant.

Therap-Cat-Vet: Preanesthetic medicant.

Keywords: Antimuscarinic; Antispasmodic

///////////Glycopyrrolate Tosylate, DRM-04 , DRM-04B , FDA 2018, Qbrexza

CC1=CC=C(C=C1)S(=O)(=O)[O-].C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C

FDA approves new kind of treatment Lumoxiti (moxetumomab pasudotox-tdfk) for hairy cell leukemia

September 14, 2018 8:44 am / Leave a comment

FDA approves new kind of treatment for hairy cell leukemia

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620448.htm?utm_campaign=09132018_PR_FDA%20approves%20new%20kind%20of%20treatment%20for%20hairy%20cell%20leukemia&utm_medium=email&utm_source=Eloqua&elqTrackId=05B63D7E81379E2CC560EE973164BE19&elq=584beb7f43934e57986c43f812ddeb3a&elqaid=5060&elqat=1&elqCampaignId=4039

September 13, 2018

Release

The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals.

///////////// Lumoxiti, moxetumomab pasudotox-tdfk, fda 2018, Fast Track, Priority Review designations, Orphan Drug designation,

Lanadelumab, ラナデルマブ

September 11, 2018 1:32 pm / Leave a comment

(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS HYIMMWVRQA PGKGLEWVSG IYSSGGITVY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAYRR IGVPRRDEFD IWGQGTMVTV
SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL
GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR
EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS
RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIS SWLAWYQQKP GKAPKLLIYK ASTLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNTYWTFGQG TKVEIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; dishulfide bridge: H22-H96, H149-H205, H225-L213, H231-H’231, H234-H’234, H266-H326, H372-H430, H’22-H’96, H’149-H’205, H’225-L’213, H’266-H’326, H’372-H’430, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Lanadelumab

DX 2930

Fda approved 2018/8/23, Takhzyro

Formula	C6468H10016N1728O2012S48
Cas	1426055-14-2
Mol weight	145714.225

Peptide, Monoclonal antibody
Prevention of angioedema in patients with hereditary angioedema

Immunomodulator, Plasma kallikrein inhibitor

breakthrough therapy, UNII: 2372V1TKXK

Image result for Lanadelumab

Lanadelumab (INN) (alternative identifier DX-2930^[1]) is a human monoclonal antibody (class IgG1 kappa)^[2] that targets plasma kallikrein (pKal)^[1] in order to promote prevention of angioedema in patients with hereditary angioedema.^[3]^[4] In phase 1 clinical trialsLanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of patients with hereditary angioedeman and decrease the number of patients experiencing attacks of angioedema.^[1]^[5]^[6]^[7] As of 2017 ongoing trials for Lanadelumab include two phase 3 studies focused on investigating the utility of Lanadelumab in preventing of acute angioedema attacks in hereditary angioedema patients^[8]^[9]

Image result for Lanadelumab

This drug was produced by Dyax Corp and currently under development by Shire.^[10] Lanadelumab has been designated by the U.S. Food and Drug Administration (FDA) as a breakthrough therapy.^[11]

Image result for Lanadelumab

References

^ Jump up to:^a ^b ^c Banerji, Aleena; Busse, Paula; Shennak, Mustafa; Lumry, William; Davis-Lorton, Mark; Wedner, Henry J.; Jacobs, Joshua; Baker, James; Bernstein, Jonathan A. (2017-02-23). “Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis”. The New England Journal of Medicine. 376 (8): 717–728. doi:10.1056/NEJMoa1605767. ISSN 1533-4406. PMID 28225674.
Jump up^ Kenniston, Jon A.; Faucette, Ryan R.; Martik, Diana; Comeau, Stephen R.; Lindberg, Allison P.; Kopacz, Kris J.; Conley, Gregory P.; Chen, Jie; Viswanathan, Malini (2014-08-22). “Inhibition of Plasma Kallikrein by a Highly Specific Active Site Blocking Antibody”. The Journal of Biological Chemistry. 289 (34): 23596. doi:10.1074/jbc.M114.569061. PMC 4156074 . PMID 24970892.
Jump up^ Statement On A Nonproprietary Name Adopted By The USAN Council – Lanadelumab, American Medical Association.
Jump up^ World Health Organization (2015). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 114”(PDF). WHO Drug Information. 29 (4).
Jump up^ Chyung, Yung; Vince, Bradley; Iarrobino, Ryan; Sexton, Dan; Kenniston, Jon; Faucette, Ryan; TenHoor, Chris; Stolz, Leslie E.; Stevens, Chris (2014-10-01). “A phase 1 study investigating DX-2930 in healthy subjects”. Annals of Allergy, Asthma & Immunology. 113 (4): 460–466.e2. doi:10.1016/j.anai.2014.05.028. ISSN 1534-4436. PMID 24980392.
Jump up^ “A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2017-03-24.
Jump up^ “Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema (HAE) Subjects – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2017-03-24.
Jump up^ “Efficacy and Safety Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2017-03-24.
Jump up^ “Long-term Safety and Efficacy Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2017-03-24.
Jump up^ “Lanadelumab – AdisInsight”. adisinsight.springer.com. Retrieved 2017-03-24.
Jump up^ “Dyax Corp. Receives FDA Breakthrough Therapy Designation for DX-2930 for Prevention of Attacks of Hereditary Angioedema”. http://www.businesswire.com. Retrieved 2017-03-24.

Lanadelumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	kallikrein
Clinical data
Synonyms	DX-2930
ATC code	none
Identifiers
CAS Number	1426055-14-2
ChemSpider	none
UNII	2372V1TKXK
Chemical and physical data
Formula	C₆₄₆₈H₁₀₀₁₆N₁₇₂₈O₂₀₁₂S₄₇
Molar mass	145.7 kDa

///////////Lanadelumab, Peptide, Monoclonal antibody, FDA 2018, ラナデルマブ ,Immunomodulator, Plasma kallikrein inhibitor, DX 2930, breakthrough therapy, Takhzyro

“DRUG APPROVALS INTERNATIONAL” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Monoclonal antibodies for the immune system

Immune system (“-l(i[m])-“)

Human (“-limu-“)	Immunosuppression: Abrilumab Adalimumab Anifrolumab^† Atorolimumab Avelumab Belimumab Bleselumab Brodalumab Camidanlumab tesirine Carlumab Cemiplimab Dupilumab Eldelumab Emapalumab^† Fresolimumab Gimsilumab Golimumab Lanadelumab Lenzilumab Lerdelimumab Lirilumab Mavrilimumab Metelimumab Morolimumab Namilumab Oleclumab Oxelumab§ Pamrevlumab Placulumab Sarilumab Sifalimumab Tabalumab Tezepelumab^† Ulocuplumab Varlilumab Immune activation: Ipilimumab Atezolizumab Durvalumab Nivolumab Pembrolizumab Tremelimumab^† Urelumab Other: Bertilimumab Zanolimumab
Mouse (“-limo-“)	Afelimomab Elsilimomab Faralimomab Gavilimomab Inolimomab Maslimomab Nerelimomab Odulimomab Telimomab aritox Vepalimomab Zolimomab aritox
Chimeric (“-lixi-“)	Andecaliximab^† Basiliximab Clenoliximab Galiximab Gomiliximab Infliximab Keliximab Lumiliximab Priliximab Teneliximab Vapaliximab
Humanized (“-lizu-“)	Immunosuppressive: Aselizumab Apolizumab^§ Benralizumab Cedelizumab Certolizumab pegol Crizanlizumab^† Daclizumab Eculizumab Efalizumab Epratuzumab Erlizumab Etrolizumab^† Fontolizumab Inebilizumab^† Itolizumab Lampalizumab^† Letolizumab Ligelizumab Lulizumab pegol Mepolizumab Mogamulizumab Natalizumab Ocrelizumab Omalizumab Ozoralizumab Pascolizumab Pateclizumab Pembrolizumab Pexelizumab Pidilizumab Plozalizumab PRO 140^† Quilizumab Ravulizumab^† Reslizumab Rontalizumab Rovelizumab Ruplizumab Samalizumab Siplizumab Talizumab Teplizumab Tibulizumab Tislelizumab Tocilizumab Toralizumab Tregalizumab Vatelizumab Vedolizumab Visilizumab Vobarilizumab TGN1412^§ Non-immunosuppressive: Ibalizumab
Chimeric + humanized (“-lixizu-“)	Otelixizumab Tavolimab
Veterinary (“-lvet-“)	Gilvetmab

Interleukin (“-k(i[n])-“)

Human (“-kinu-“)	Brazikumab Briakinumab Canakinumab Fezakinumab Fletikumab Guselkumab Secukinumab Sirukumab Tralokinumab^† Ustekinumab
Humanized (“-kizu-“, “-kinzu-“)	Anrukinzumab Clazakizumab Enokizumab Gevokizumab Ixekizumab Mirikizumab Lebrikizumab Olokizumab^† Perakizumab Risankizumab^† Tildrakizumab
Veterinary (“-kivet-“)	Lokivetmab

Inflammatory lesions (“-les-“)

Mouse (“-leso-“)	Besilesomab Fanolesomab^‡ Lemalesomab Sulesomab

^#WHO-EM
^‡Withdrawn from market
Clinical trials:
- ^†Phase III
- ^§Never to phase III

Sodium zirconium cyclosilicate, ナトリウムジルコニウムシクロケイ酸塩

September 10, 2018 1:50 pm / Leave a comment

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Sodium zirconium cyclosilicate

ZS-9, ZS 9, UZSi-9

CAS 242800-27-7, H₂ O₃ Si . x H₂ O . ²/₃ Na . ¹/₃ Zr, Sodium zirconium cyclosilicate; Silicic acid (H2SiO3), Sodium zirconium(4+) salt (3:2:1), hydrate

USAN CAS 17141-74-1, H₆ O₉ Si₃ . 2 Na . Zr, Silicic acid (H₂SiO₃), sodium zirconium(4+) salt (3:2:1), hydrate, Sodium zirconium silicate (Na₂ZrSi₃O₉) hydrate

ナトリウムジルコニウムシクロケイ酸塩

ZrH4O6. 3H4SiO4. 2H2O. 2Na, 561.6068, AS IN kegg

Molecular Formula, H6-O9-Si3.2Na.Z, Molecular Weight, 371.5004 as in chemid plus

APPROVED FDA 2018/5/18, LOKELMA, NDA 207078

APPROVED EMA 2018/3/22, LOKELMA

ATC code: V03AE10

UNII-D652ZWF066

TREATMENT	selective cation exchanger Treatment of hyperkalemia

Sodium zirconium cyclosilicate (ZS-9) is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma and AstraZeneca for the treatment of hyperkalemia (elevated serum potassium levels).^[1]

The product was originated at ZS Pharma, a wholly owned subsidiary of AstraZeneca. In 2015, ZS Pharma was acquired by AstraZeneca.

Hyperkalaemia is the presence of an abnormally high concentration of potassium in the blood. Most data on the occurrence of hyperkalaemia have been obtained from studies of hospitalised patients, and the incidence ranges from 1 to 10%. There is no agreed definition of hyperkalaemia, since the raised level of potassium at which a treatment should be initiated has not been established. The European Resuscitation Council guidelines consider hyperkalaemia to be a serum potassium (S-K) level > 5.5 mmol/L, with mild elevations defined as 5.5 to 5.9 mmol/L, moderate as 6.0-6.4 mmol/L, and severe as ≥ 6.5 mmol/L. The guidelines also note that extracellular potassium levels are usually between 3.5 and 5.0 mmol/L, which is considered the normal range for adults. However, a number of recent retrospective studies have shown the risk of mortality is increased even with only modest elevations of S-K. Mortality risk has been shown to be significantly higher in chronic kidney disease (CKD) patients with S-K levels > 5.0 mmol/L. In acute myocardial infarction patients, a mean postadmission S-K ≥ 5.5 mmol/L during hospitalisation corresponded to a 12-fold increase in death compared with S-K levels between 3.5 and 4.5 mmol/L but, more importantly, S-K levels between 4.5 and 5.0 mmol/L, which is within the normal range, were associated with a 2-fold increased risk of mortality compared with S-K between 3.5 and 4.5 mmol/L.

Sodium zirconium cyclosilicate (ZS) has been developed as treatment for hyperkalaemia. The indication applied for is: Treatment of hyperkalaemia in adult patients, acute and extended use. ZS is an inorganic cation exchange crystalline compound. ZS has a high capacity to selectively entrap monovalent cations, specifically excess potassium and ammonium ions, over divalent cations such as calcium and magnesium, in the gastrointestinal tract. The high specificity of ZS for potassium is attributable to the chemical composition and diameter of the micro pores, which act in an analogous manner to the selectivity filter utilized by physiologic potassium channels. The exchange with potassium ions occurs throughout the gastrointestinal tract with onset in the upper part of the gastrointestinal tract. The trapped potassium ions are excreted from the body via the faeces, thereby reducing any excess and resolving hyperkalaemia. As claimed by the applicant, ZS demonstrates improved capacity, selectivity, and speed for entrapping excess potassium over currently available options for the treatment of hyperkalaemia. The proposed commercial formulation of ZS is a non-absorbed, insoluble, white crystalline powder for suspension with a specific particle size distribution profile. The proposed starting dose of ZS for reversal of hyperkalaemia (when serum potassium is > 5.0 mmol/l) is up to 10 g/day, divided in 3 doses (TID) to achieve normokalaemia.

EMA

The chemical name of the active substance is hydrogen sodium zirconium (IV) silicate hydrate. Due to the natural variability in the manufacturing process of the active substance, it is expected to have the formula Na~1.5H~0.5ZrSi3O9 • 2–3 H2O and relative molecular mass in the range of 390.5 – 408.5. The WHO chose not to designate an INN for the active substance, and a USAN sodium zirconium cyclosilicate is used throughout the dossier and this CHMP AR. The active substance has the following structure:

Figure 1. Stick-and-ball (left) and polyhedral (right) unit cell structural representation of the main framework of the microporous sodium zirconium cyclosilicate active substance. Red = zirconium, green = silicon, blue = oxygen atoms. Cations are not pictured.

The structure of sodium zirconium cyclosilicate is a cubic cell arrangement of octahedrally coordinated Zr and tetrahedrally coordinated Si units that interconnect through oxygen bridges as Zr–O–Si and Si–O–Si. The two types of units are observed in a ratio 1:3, respectively, and repeat orderly to form a three-dimensional framework characteristic of the compound. The framework acquires its negative charge from the octahedral fractions, [ZrO6]2– , and features channels and cavities that interconnect and locate the positive ions that counter-balance the negative charge of the framework. Electrostatic interactions between the framework and the cations allow for mobility and possibility of exchange with other cations that would fit and pass the free pore openings of ~ 3.0 Å. The uniform micropore structure allows a high exchange capacity and selectivity for potassium (K+) and ammonium (NH4 +) cations, providing the compound with its distinctive ion-exchange selectivity features responsible for its mode of action. In vitro characterisation of ion selectivity of sodium zirconium cyclosilicate was provided by the applicant and considered satisfactory

The structure of sodium zirconium cyclosilicate was confirmed using synchrotron powder diffraction, standard X-ray powder diffraction, 29Si magic angle spinning solid nuclear magnetic resonance studies (29Si-MASNMR), Fourier transform infrared spectroscopy, inductive coupled plasma-optical emission spectrometry, wave dispersive X-ray microprobe analysis and thermo-gravimetric analysis. Calculations using proprietary software were also used for structure elucidation. The active substance is a white crystalline powder. Bonding interactions in the main framework are considered primarily of covalent nature, with some ionic contribution due to the difference in electronegativity between Si–O and Zr–O. The covalent bonding interactions in all directions within the crystals make sodium zirconium cyclosilicate a compound insoluble in water or in organic solvents. It is neither hygroscopic nor sensitive to light and it is resistant to heat. During the hydrothermal synthesis, the possibility that other crystalline phases are formed exists. The observed crystalline forms are controlled by the manufacturing process parameters and release specifications. Sodium zirconium cyclosilicate is considered to be a new active substance. The applicant demonstrated that neither it, nor its derivatives have ever been active substances in medicinal products authorised in the EU………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004029/WC500246776.pdf

TGA

DOC]Australian Public Assessment Report for Sodium zirconium … – TGA

https://www.tga.gov.au/…/auspar-sodium-zirconium-cyclosilicate-hydrate-180129.doc…

Jan 29, 2018 – The sponsor has submitted an application to register a new chemical entity Lokelma,sodium zirconium cyclosilicate hydrate powder for …

The chemical formula of sodium zirconium cyclosilicate hydrate is Na~1.5H~0.5ZrSi₃O₉.2-3H₂O.

The drug substance ‘sodium zirconium cyclosilicate hydrate’ (abbreviated to ZS) is a white crystalline powder. The structure of ZS is summarised as a cubic cell arrangement of octahedrally coordinated zirconium Zr ([ZrO₆]^2-) and tetrahedrally coordinated silicon Si ([SiO₄]0) units that interconnect through oxygen bridges as Zr-O-Si and Si-O-Si. The two types of units are observed in a ratio of 1:3, respectively, and repeat orderly to form a three dimensional framework characteristic of the compound. The framework acquires its negative charge from the octahedral fractions, [ZrO₆]^2- and features channels and cavities that interconnect and locate the positive ions (sodium, Na⁺, and hydrogen, H⁺) that counter balance the negative charge of the framework.

The manufacturing process is tightly controlled in terms of order of addition of starting material, reaction and crystallisation temperatures, mixing speeds and times, and minimum number of rinses, in order to meet expected yields of the drug substance of an expected quality. In process quality control tests [information redacted] are applied during the manufacturing process to ensure the formation of the correct crystalline structure and batch to batch consistency.

Sodium zirconium cyclosilicate hydrate is completely insoluble.

The drug substance forms part of a family of zirconium silicates that have specific ion exchange properties. Its mechanism of action is based on the cations within its porous crystalline structure, and their ability to freely exchange with a select group of monovalent cations, most specifically the potassium (K⁺) and ammonium (NH⁴⁺) cations. The pore size within the three dimensional crystalline structure has been measured at ~3Å (2.4 x 3.5 Å^[1]), which is sufficiently wide enough to trap the potassium monovalent cations which have an approximate ionic diameter of 2.98Å.

The particle size of the drug substance is controlled to maintain a non-systemic mode of action. The sponsor adequately justified not routinely controlling the size of larger particles in the drug substance as differences in particle size were shown to not affect performance as measured by potassium ion exchange capacity (KEC), and there was no correlation between KEC and D90 for clinical lots manufactured.

There are two alternate zirconium silicate crystalline phases which may be formed in the reaction process; Crystalline Phase A (CPA) and Crystalline Phase B (CPB). These layered, two-dimensional structures also exhibit ion exchange properties, although their ion selectivity is less specific for the potassium K⁺ cations compared to the desired drug substance. PXRD techniques are used to differentiate between the desired drug substance and levels of CPA and CPB. Appropriate limits are applied in the drug substance specification to limit the content of these crystalline phases in the drug substance/drug product.

The quality of the drug substance is controlled by an acceptable specification that includes test and limits for Appearance, Identification (by FTIR and PXRD), KEC , Crystalline Phase A , Crystalline Phase B , Zirconium content , Silicon content , Hafnium content , Moisture content , Particle Size , and Elemental Impurities.

^[1] 1 Å = 0.1 nm.

Image result for Sodium zirconium cyclosilicate

Background

Hyperkalemia occurs in 3 to 10% of hospitalized patients^[2] but is often mild. Hyperkalemia can arise from impaired renal function, potassium-sparing diuretics and renin–angiotensin system blockers (e.g., ACE inhibitors, angiotensin receptor blockers, spironolactone) and diabetes mellitus.^[2]^[3]^[4]^[5]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.^[6] However, if hyperkalemia causes any ECG change it is considered a medical emergency^[6] due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently.^[6] serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.^[6]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.^[2] However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is a secondary effect that denotes significant underlying medical problems.^[2] Accordingly, these problems are both proximate and ultimate causes of death,^[2] and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factorfor cardiovascular mortality.^[7]

Several approaches are used in the treatment of hyperkalemia.^[6] In October 2015, the U.S. Food and Drug Administration (FDA) approved patiromer which works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange. Previously, the only approved product was sodium polystyrene sulfonate (Kayexalate),^[8] an organic ion-exchange resin that nonspecifically binds cations (e.g., calcium, potassium, magnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate.^[9] In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.^[6]^[8]^[10]^[11]

Mechanism of action

Cross-sections of ZS-9 pores with three different ions (K⁺ = potassium, Na⁺ = sodium, Ca²⁺ = calcium). The specificity for potassium is thought to be caused by the diameter and composition of the pores, which resembles potassium channels.

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.^[12] 11 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions, presumably by mimicking the actions of physiologic potassium channels.^[13] ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized.

Clinical studies

A phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation).^[14]

A double-blind, phase 3 clinical trial in 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.^[15] Patients were randomly assigned to receive either ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3 times daily for 48 hours (acute phase). Patients who achieved normokalemia (serum potassium of 3.5-4.9 mmol/L) were randomly assigned to receive ZS-9 or placebo once daily for 12 additional days (maintenance phase). At the end of the acute phase, serum potassium significantly decreased in the 2.5 g, 5 g, and 10 g ZS-9 groups. During the maintenance phase, once daily 5 g or 10 g ZS-9 maintained serum potassium at normal levels. Adverse events, including specifically gastrointestinal effects, were similar with either ZS-9 or placebo.^[15]

A double-blind, phase 3 clinical trial in 258 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.^[16] All patients received 10 g ZS-9 three times daily for 48 hours in the initial open-label phase. Patients who achieved normokalemia (serum potassium 3.5-5.0 mEq/L) were randomly assigned to receive either ZS-9 (5 g, 10 g, or 15 g) or placebo once daily for 28 days (double-blind phase). 98% of patients (n=237) achieved normokalemia during the open-label phase. During the double-blind phase, once daily 5 g, 10 g, and 15 g ZS-9 maintained serum potassium at normal levels in a significantly higher proportion of patients (80%, 90%, and 94%, respectively) than placebo (46%). Adverse events were generally similar with either ZS-9 or placebo. Hypokalemiaoccurred in more patients in the 10 g and 15 g ZS-9 groups (10% and 11%, respectively), versus none in the 5 g ZS-9 or placebo groups.^[16]

Regulatory

In the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration in May 2016 due to issues associated with manufacturing.^[17] On May 18th, 2018, the FDA approved ZS-9 (now known as Lokelma®) for treatment of adults with hyperkalemia.^[18]

PATENT

WO 2012109590

PATENT

WO 2015070019

https://patents.google.com/patent/WO2015070019A1/en

The present invention relates to novel zirconium silicate (“ZS”) compositions which are preferably sodium zirconium cyclosilicates having an elevated level of ZS-9 crystalline form relative to other forms of zirconium cyclosilicates (i.e., ZS-7) and zirconium silicates (i.e., ZS-8, ZS-11). The ZS compositions are preferably sodium zirconium cyclosilicate compositions where the crystalline form has at least 95% ZS-9 relative to other crystalline forms of zirconium silicate. The ZS compositions of the present invention unexpectedly exhibit a markedly improved in vivo potassium ion absorption profile and rapid reduction in elevate levels of serum potassium.

[004] Preferably ZS compositions of the present invention are specifically formulated at particular dosages to remove select toxins, e.g., potassium ions or ammonium ions, from the gastrointestinal tract at an elevated rate without causing undesirable side effects. The preferred formulations are designed to remove and avoid potential entry of particles into the bloodstream and potential increase in pH of urine in patients. The formulation is also designed to release less sodium into the blood. These compositions are particularly useful in the therapeutic treatment of hyperkalemia and kidney disease. The present invention also relates to pharmaceutical granules, tablets, pill, and dosage forms comprising the microporous ZS as an active ingredient. In particular, the granules, tablets, pills or dosage forms are compressed to provide immediate release, delayed release, or specific release within the subject. Also disclosed are microporous ZS compositions having enhanced purity and potassium exchange capacity (“KEC”). Methods of treating acute, sub-acute, and chronic hyperkalemia have also been investigated. Disclosed herein are particularly advantageous dosing regimens for treating different forms of hyperkalemia using the microporous ZS compositions noted above. In addition, the present invention relates to methods of co-administering microporous ZS compositions in combination with other pharmacologic drugs that are known to induce, cause, or exacerbate the hyperkalemic condition.

Patent

Publication numberPriority datePublication dateAssigneeTitle

US3329480A *1963-10-181967-07-04Union Oil CoCrystalline zircono-silicate zeolites

US4581141A *1978-02-271986-04-08Purdue Research FoundationDialysis material and method for removing uremic substances

US20050220752A1 *2004-03-302005-10-06Dominique CharmotIon binding polymers and uses thereof

US20110097401A1 *2009-06-122011-04-28Meritage Pharma, Inc.Methods for treating gastrointestinal disorders

US20120213847A1 *2011-02-112012-08-23ZS Pharma, Inc.Microporous zirconium silicate for the treatment of hyperkalemia

CA2084086C *1990-05-282002-10-08Steven M. KuznickiLarge-pored molecular sieves containing at least one octahedral site and tetrahedral sites of at least one type

US5338527A *1992-08-201994-08-16UopZirconium silicate composition, method of preparation and uses thereof

US5891417A *1997-04-081999-04-06Uop LlcZirconium silicate and zirconium germanate molecular sieves and process using the same

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EP1038580B1 *1999-03-262005-05-25Uop LlcAmmonium ion adsorption process using zirconium silicate and zirconium germanate molecular sieves

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WO2002062356A3 *2001-02-062002-09-26Ash Medical Systems IncMonovalent-selective cation exchangers as oral sorbent therapy

CN104968336A *2012-07-112015-10-07Zs制药公司Microporous zirconium silicate for the treatment of hyperkalemia in hypercalcemic patients and improved calcium-containing compositions for the treatment of hyperkalemia

KR20150074053A *2012-10-222015-07-01제트에스 파마, 인코포레이티드Microporous zirconium silicate for treating hyperkalemia

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Family To Family Citations

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References

Jump up^ “ZS-9. A selective potassium binder”. ZS-Pharma.
^ Jump up to:^a ^b ^c ^d ^e Elliott, M. J.; Ronksley, P. E.; Clase, C. M.; Ahmed, S. B.; Hemmelgarn, B. R. (2010). “Management of patients with acute hyperkalemia”. Canadian Medical Association Journal. 182 (15): 1631–5. doi:10.1503/cmaj.100461. PMC 2952010 . PMID 20855477.
Jump up^ Stevens, M. S.; Dunlay, R. W. (2000). “Hyperkalemia in hospitalized patients”. International Urology and Nephrology. 32 (2): 177–80. doi:10.1023/A:1007135517950. PMID 11229629.
Jump up^ Navaneethan, S. D.; Yehnert, H.; Moustarah, F.; Schreiber, M. J.; Schauer, P. R.; Beddhu, S. (2009). “Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis”. Clinical Journal of the American Society of Nephrology. 4 (10): 1565–74. doi:10.2215/CJN.02250409. PMC 2758256 . PMID 19808241.
Jump up^ Tamirisa, K. P.; Aaronson, K. D.; Koelling, T. M. (2004). “Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure”. American Heart Journal. 148(6): 971–8. doi:10.1016/j.ahj.2004.10.005. PMID 15632880.
^ Jump up to:^a ^b ^c ^d ^e ^f Taal, M.W.; Chertow, G.M.; Marsden, P.A.; Skorecki, K.; Yu, A.S.L.; Brenner, B.M. (2012). Brenner and Rector’s The Kidney (Chapter 17, page 672, 9th ed.). Elsevier. ISBN 978-1-4160-6193-9.
Jump up^ Fang, J.; Madhavan, S.; Cohen, H.; Alderman, M. H. (2000). “Serum potassium and cardiovascular mortality”. Journal of General Internal Medicine. 15 (12): 885–90. doi:10.1046/j.1525-1497.2000.91021.x. PMC 1495719 . PMID 11119186.
^ Jump up to:^a ^b Watson, M.; Abbott, K. C.; Yuan, C. M. (2010). “Damned if You Do, Damned if You Don’t: Potassium Binding Resins in Hyperkalemia”. Clinical Journal of the American Society of Nephrology. 5 (10): 1723–6. doi:10.2215/CJN.03700410. PMID 20798253.
Jump up^ Emmett, M.; Hootkins, R. E.; Fine, K. D.; Santa Ana, C. A.; Porter, J. L.; Fordtran, J. S. (1995). “Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion”. Gastroenterology. 108 (3): 752–60. doi:10.1016/0016-5085(95)90448-4. PMID 7875477.
Jump up^ Sterns, R. H.; Rojas, M.; Bernstein, P.; Chennupati, S. (2010). “Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?”. Journal of the American Society of Nephrology. 21 (5): 733–5. doi:10.1681/ASN.2010010079. PMID 20167700.
Jump up^ Kamel, K. S.; Schreiber, M. (2012). “Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?”. Nephrology Dialysis Transplantation. 27(12): 4294–7. doi:10.1093/ndt/gfs293. PMID 22989741.
Jump up^ Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
Jump up^ =Stavros, F (2014). “Characterization of Structure and Function of ZS-9, a K⁺ Selective Ion Trap”. PLOS ONE. 9 (12): e114686. doi:10.1371/journal.pone.0114686. PMC 4273971 . PMID 25531770.
Jump up^ Ash SR, et al. “Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients.” American Society of Nephrology 2013 conference, Late-Breaking Abstract.
^ Jump up to:^a ^b Packham DK, et al. (2014). “Sodium zirconium cyclosilicate in hyperkalemia”. New England Journal of Medicine. 372 (3): 222–31. doi:10.1056/NEJMoa1411487. PMID 25415807.
^ Jump up to:^a ^b Kosiborod M, et al. (2014). “Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia”. Journal of the American Medical Association. 312 (21): 2223–33. doi:10.1001/jama.2014.15688. PMID 25402495.
Jump up^ Ben Adams (May 27, 2016). “AstraZeneca’s $2.7B hyperkalemia drug ZS-9 rejected by FDA”. FierceBiotech.
Jump up^ https://www.drugs.com/history/lokelma.html

Sodium zirconium cyclosilicate
Clinical data
Crystal structure of ZS-9. Blue spheres = oxygen atoms, red spheres = zirconium atoms, green spheres = silicon atoms.
Trade names	Lokelma
Routes of administration	Oral
ATC code	none
Legal status
Legal status	US: Rx-only
Pharmacokinetic data
Bioavailability	Not absorbed
Excretion	Stool
Identifiers
IUPAC name [show]
CAS Number	242800-27-7
UNII	D652ZWF066
KEGG	D10727

//////////////Sodium zirconium cyclosilicate, ナトリウムジルコニウムシクロケイ酸塩 , FDA 2018, EMA, 2018, EU 2018, ZS 9, UZSi-9

O[Si]1(O[Si](O[Si](O1)(O)O)(O)O)O.[Na+].[Na+].[Zr

Stiripentol, スチリペントール

September 3, 2018 7:55 am / Leave a comment

ChemSpider 2D Image | Stiripentol | C14H18O3

Stiripentol

スチリペントール

STIRIPENTOL; Diacomit; 49763-96-4; BCX 2600; Estiripentol; Stiripentolum

CAS:	137767-55-6 49763-96-4

(E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ol

Molecular Formula:	C₁₄H₁₈O₃
Molecular Weight:	234.295 g/mol

UNII

R02XOT8V8I, Diacomit

fda approval 2018/8/20

Stiripentol (marketed as Diacomit by Laboratoires Biocodex) is an anticonvulsant drug used in the treatment of epilepsy. It is approved for the treatment of Dravet syndrome, an epilepsy syndrome. It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.

Medical use

It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndromewhose seizures are not adequately controlled.^[1]^[2]^[3] As of 2017 it was not known whether stiripentol remains useful as children become adolescents nor as they become adults.^[4]

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxia, hypotonia, and dystonia.^[3]

Common (between 1% and than 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.^[3]

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.^[3]

Pharmacology

As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.

Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices.^[5] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.^[6] Specifically, it has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels.^[7]

Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs’ metabolism and increasing blood plasma levels.^[3]

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1-[3,4-(methylendioxy)-phenyl]-1penten-3-ol. It is chiral and is marketed as an equimolar racemic mixture. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.^[8]

Paper

Tetrahedron: Asymmetry

Volume 24, Issues 5–6, 31 March 2013, Pages 285-289

https://www.sciencedirect.com/science/article/abs/pii/S0957416613000529

Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase catalyzed resolution and alkene metathesis

https://doi.org/10.1016/j.tetasy.2013.02.006

The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via cross metathesis of 5-vinylbenzo[d][1,3]dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.

Image result for Stiripentol synthesis

Stiripentol (CAS NO.: 49763-96-4), with other name of 4,4-Dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-ol, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Stiripentol

The synthesis of [14]-labeled stiripentol has been published:The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO₂ by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH₄ to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO₃-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol


合成路线图解说明:The condensation of 3,4-methylenedioxybenzaldehyde (I) with 3,3-dimethyl-2-butanone (II) by means of NaOH in ethanol-water gives 4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-one (III), which is reduced with NaBH4 in methanol.

合成路线图解说明:The synthesis of [14]-labeled stiripentol has been published: The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol.

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years.^[8] It was originally developed for adults with focal seizures, but failed a Phase III trial.^[4]

In December 2001 the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy of infancy (SMEI, also known as Dravet’s syndrome) in children and in 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs.^[3] It was approved in Canada for this use in 2012.^[9] As of 2017 it was also approved for this use in Japan.^[2]

As of 2014 it was not approved in the US, and parents of children with Dravets were paying around $1,000 for a month supply to obtain it from Europe.^[10]

Stiripentol
Clinical data

Trade names	Diacomit
AHFS/Drugs.com	International Drug Names
License data	EU EMA: by INN
Routes of administration	Oral
ATC code	N03AX17 (WHO)
Legal status
Legal status	AU: Unscheduled
Identifiers
IUPAC name [show]
CAS Number	49763-96-4
PubChem CID	5311454
IUPHAR/BPS	5469
ChemSpider	4470940
UNII	R02XOT8V8I
KEGG	D05928
ECHA InfoCard	100.051.329
Chemical and physical data
Formula	C₁₄H₁₈O₃
Molar mass	234.30 g·mol⁻¹
3D model (JSmol)	Interactive image

References

Jump up^ Brigo, F; Igwe, SC; Bragazzi, NL (18 May 2017). “Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy”. The Cochrane Database of Systematic Reviews. 5: CD010483. doi:10.1002/14651858.CD010483.pub4. PMID 28521067.
^ Jump up to:^a ^b Nickels, KC; Wirrell, EC (May 2017). “Stiripentol in the Management of Epilepsy”. CNS drugs. 31 (5): 405–416. doi:10.1007/s40263-017-0432-1. PMID 28434133.
^ Jump up to:^a ^b ^c ^d ^e ^f “Diacomit (stiripentol) SPC” (PDF). EMA. 8 January 2014. Retrieved 1 October 2017. For updates see EMA index page
^ Jump up to:^a ^b Nabbout, R; Camfield, CS; Andrade, DM; Arzimanoglou, A; Chiron, C; Cramer, JA; French, JA; Kossoff, E; Mula, M; Camfield, PR (April 2017). “Treatment issues for children with epilepsy transitioning to adult care”. Epilepsy & Behavior. 69: 153–160. doi:10.1016/j.yebeh.2016.11.008. PMID 28188045.
Jump up^ Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H (2006). “Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels”. Epilepsia. 47 (4): 704–16. doi:10.1111/j.1528-1167.2006.00497.x. PMID 16650136.
Jump up^ Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). “Stiripentol. A novel antiepileptic drug” (PDF). Pharmacological reports : PR. 57 (2): 154–60. PMID 15886413.
Jump up^ Sada N, Lee S, Katsu T, Otsuki T, Inoue T (2015). “Targeting LDH enzymes with a stiripentol analog to treat epilepsy”. Science. 347 (6228): 1362–67. doi:10.1126/science.aaa1299. PMID 25792327.
^ Jump up to:^a ^b “Scientific evaluation” (PDF). EMA. 2007.
Jump up^ “Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome)” (PDF). Canadian Agency for Drugs and Technologies in Health. April 2015.
Jump up^ Kossoff, E (January 2014). “Stiripentol for dravet syndrome: is it worth it?”. Epilepsy Currents. 14 (1): 22–3. doi:10.5698/1535-7597-14.1.22. PMC 3913306 . PMID 24526870.

////////////Stiripentol, fda 2018, Diacomit, 49763-96-4, BCX 2600, Estiripentol, Stiripentolum

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